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IL-7 in human health and disease.

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  • 1. Pediatric Oncology Branch, National Cancer Institute, 10 Center Drive, Bethesda, MD 20892, United States.
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    • Lundström W 1
    (1 author)

Seminars in Immunology, 10 Mar 2012, 24(3):218-224
https://doi.org/10.1016/j.smim.2012.02.005 PMID: 22410365 PMCID: PMC3358500

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Abstract 

IL-7 plays many essential roles in human health and disease. Congenital deficiencies in IL-7 signaling result in profound immunodeficiency, polymorphisms in IL7Rα modulate susceptibility to autoimmune disease, and acquired somatic activating mutations in IL7Rα contribute to neoplastic transformation in B cell and T cell leukemia. In response to lymphopenia, IL-7 accumulates to supranormal levels, which alters T cell homeostasis by augmenting T cell reactivity toward self and cognate antigens. This physiologic response is now routinely exploited to improve the efficacy of adoptive cell therapies for cancer. Clinical trials of recombinant IL-7 have demonstrated safety and potent immunorestorative effects, and current studies are investigating whether rhIL-7 therapy can improve outcomes in chronic viral infection and in the context of cancer immunotherapies. Building upon the large fund of knowledge regarding the basic biology of IL-7, this review will discuss the many and varied roles of IL-7 in human health and disease.

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Semin Immunol. Author manuscript; available in PMC 2013 Jun 1.
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PMCID: PMC3358500
NIHMSID: NIHMS360289
PMID: 22410365

IL-7 IN HUMAN HEALTH AND DISEASE

Wangko Lundström,a Natasha Fewkes,a and Crystal L. Mackalla,*
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1. Introduction

The same mechanisms and pathways utilized by the immune system to respond to infection, lymphopenia and cancer can also predispose to autoimmunity and can be hijacked by cancer cells to support their uncontrolled proliferation. IL-7’s essential properties as a required factor for lymphocyte development and modulator of T cell homeostasis make it an attractive candidate for modulating immunodeficiency and augmenting immune based therapies, but also render it a plausible culprit in human disease. Indeed, dysregulated IL-7 signaling is a co-factor in several autoimmune diseases and in lymphoid cancers, while treatment with recombinant human IL-7 (rhIL-7) is showing promise in several clinical settings. This review will discuss known roles for IL-7 in human health (sections 2 & 3) and disease (sections 4, 6 & 7), and review results of ongoing clinical trials with rhIL7 (section 5).

2. IL-7 in Human Lymphocyte Development

2.1 IL-7 in T-Cell Development

Humans born with loss of function mutations in IL7R (IL7Rα, CD127), IL2RG (γc, CD132), or JAK3, present during infancy with a syndrome of severe combined immunodeficiency (SCID), characterized by opportunistic infection, rash, diarrhea and failure to thrive[1–4]. Without bone marrow transplantation or gene replacement therapy, the condition is fatal[1, 5]. Immunodeficiency associated with IL7R mutations results in an absence of T cells with relatively normal numbers of NK cells and B cells (T–B+NK+ SCID)[2], in contrast to SCID caused by IL2RG or JAK3 mutations, which results in a T−B+NK− phenotype, due to concomitantly impaired IL15 signaling[1]. Hypomorphic IL7R mutations result in severe T cell deficiency, whereas hypomorphic mutations in IL2RG result in a milder phenotype[6], emphasizing the essential and non-redundant role for IL7R mediated signaling in human T cell development.

2.2 IL-7 in B-Cell Development

In contrast to the severe T cell deficiency, infants with IL7R mutations have normal numbers of circulating B cells[1, 7]. The observation that IL-7 is dispensable for human B cell development has been a point of consternation, since IL-7 is required for B cell development in mice[8, 9]. Despite this clear evidence for cytokine redundancy in utero and in infancy, several lines of evidence implicate IL-7 as an important contributor to normal human B cell development. IL-7Rα expression is highly regulated during human B cell developmental stages, expressed on common lymphoid progenitors and pre-B cells, then rapidly down regulated on pro-B cells and remaining absent on mature B cells. Ex vivo cultures demonstrate potent effects of IL-7 on human early B cell progenitors[10–12], including suppression of premature Ig light-chain rearrangement in the early stages of B cell development[13]. Interestingly, IL-7 independent B cell development in a fully human ex vivo model can be accomplished using umbilical cord blood, but not when progenitors are derived from adult bone marrow[12], raising the prospect that the cytokine redundancy uncovered by congenital deficiency may not necessarily translate into a capacity for IL-7 independent generation of B cells throughout life.

Further evidence implicating a role for IL-7 during normal human B cell development comes from clinical studies where individuals are exposed to supraphysiologic levels of IL-7. In both HIV infection and idiopathic CD4+ lymphopenia, increased levels of immature/transitional B cells are observed in the peripheral blood[14, 15], at levels that are quantitatively correlated with the degree of physiologic elevations in IL-7 present. The most direct evidence for IL-7’s role in human B cell development comes from rhIL-7 induced expansion of immature/transitional B cells observed during a Phase I trial of rhIL-7[16]. RhIL-7 treated patients showed significant increases in CD19+CD10+ B cells in the peripheral blood, but no significant change in the number of mature B cells. Several patients also showed dramatic polyclonal expansion of early pre-B cells in the bone marrow, which rapidly normalized following completion of the rhIL-7 therapy. Thus, IL-7 is not absolutely required for primary B cell development in humans, but a substantial body of evidence implicates IL-7 in normal human B cell development and increased IL-7 signaling can potently expand early B cell progenitors. Not surprisingly therefore, emerging evidence implicates activating mutations in IL-7Rα in B cell precursor acute lymphoblastic leukemia (discussed in section 7.2).

3. IL-7 As a Modulator of Human T Cell Homeostasis

In addition to IL-7’s critical roles in primary lymphocyte development, murine and human studies also implicate IL-7 as an essential modulator of peripheral T cell homeostasis. Receptors for most γc cytokines are induced upon T cell activation, but the IL-7R complex is expressed continuously on most resting human T cells, with high level expression on naïve and central memory cells, lower level expression on regulatory CD4+FOXP3+ cells[17, 18], and low to absent expression on activated effectors and terminally differentiated senescent cells. Since IL-7 is continuously produced by stromal cells and circulates in picomolar concentrations[19], most human T cells are continuously exposed to IL-7 at levels sufficient to induce signaling. Murine studies demonstrate that this “trophic” IL-7 signaling provides requisite survival signals for T cell survival as adoptive transfer of cells into IL-7 deficient hosts results in severely impaired T cell survival[20]. Limitations of studies in the human model system prevent formal proof of a similar role in humans, but a substantial amount of evidence implicates IL-7 as a major modulator of peripheral T cell homeostasis in humans. The IL-7R complex is also widely expressed on a family of cells termed “innate lymphoid cells” that include populations responsible for secondary lymphoid organ development[21] as well as recently described CD4+ and CD8+ stem cell memory cells, which possess superior proliferative and renewal capacity compared to other effector/memory populations[22].

4. IL-7 during lymphopenia

Following a lymphopenia inducing insult or in the setting of congenital or acquired immunodeficiency associated with lymphopenia, patients experience elevated circulating and tissue levels of IL-7, with strong inverse correlations between circulating IL-7 levels and CD4+ T cell numbers[19, 23, 24]. Circulating IL-7 levels in healthy humans typically range from 2–8 pg/ml, but levels as high as 60 pg/ml can be observed during lymphopenia. Paradoxically, IL-7 production is actually decreased during lymphopenia due to a regulatory feedback loop mediated by IL7Rα on stromal cells, and therefore lymphopenia induced elevations result from decreased utilization[25]. Animal models demonstrate that increased IL-7 availability that occurs during lymphopenia plays a major role in mediating the enhanced cycling of naïve and memory T cells, and the increased responses to cognate and low affinity antigens seen in this setting[26–29]. Following recovery of CD4+ T cell populations, elevated IL-7 levels are cleared via IL7Rα receptor-mediated clearance and circulating levels return to normal[19, 30]. Similar inverse relationships between growth factor levels and target cell numbers are observed between erythropoietin and red blood cells[31], thrombopoietin and platelets[32] and granulocyte colony-stimulating factor (G-CSF) and neutrophils[33].

5. RhIL-7 in Clinical Trials

Direct evidence that supraphysiologic levels of IL-7 mediate alterations in human T cell homeostasis comes from studies of the effects of rhIL-7 administered in early phase clinical trials. Four Phase I trials have administered increasing doses of rhIL-7 (range 10–60 mcg/kg) to patients with refractory cancer or HIV infection[16, 34–37]. Thus far, the agent has been well tolerated, inducing only mild constitutional symptoms and no evidence for the capillary leak syndrome observed with rhIL-2 therapy [32, 33]. In each of the studies, rhIL-7 induced dose dependent increases in circulating T cell populations, with preferential expansion of recent thymic emigrants, naïve T cells and central memory T cells compared to other subsets. These changes in peripheral blood T cells reflect changes in total body T cell numbers, since FDG positron emission tomography demonstrates increased metabolic activity within secondary lymphoid organs and CT scanning demonstrates increased size of both spleen and lymph nodes at the time of peak peripheral blood expansions[35].

Patients treated with rhIL-7 show diversification of their TCR repertoire, primarily due to intense, preferential cycling of recent thymic emigrants and naïve cells, although augmentation of thymopoiesis may also contribute in some circumstances[35, 37]. The enhanced cell cycling of T cell subsets is notable. Whereas under normal conditions only approximately 5% of circulating T cells are dividing (as evidenced by Ki-67 expression), more than 50% of the circulating T cell pool becomes Ki-67+ following rhIL-7 therapy[37]. Interestingly, repetitive dosing leading to very high levels of rhIL-7 results in widespread down regulation of IL7Rα, which limits ongoing T cell cycling and provides a theoretical safety mechanism against “overdose”. RhIL-7 therapy mediates prolonged effects, likely due to both a relatively long T1/2, (range ~7–23 hours, with wide variability) as well as pharmacodynamic effects that remain well past clearance of the cytokine[16, 36]. Although cycling rates return to baseline relatively rapidly following IL7Rα down regulation and/or clearance of the cytokine, rises in circulating CD4+ and CD8+ T cell numbers remain for weeks to months after completion of rhIL-7 therapy[37].

Unlike naïve and central memory cells, some T cell subsets do not undergo substantial expansion with rhIL-7 therapy. Notably, CD4+FOXP3+ regulatory T cells show only minimal expansion, and as a result, rhIL-7 treated patients experience substantial decreases in the relative frequency of regulatory T cells within the peripheral T cell pool[34, 35]. Effector memory cells and senescent populations also show minimal expansion with rhIL-7 therapy, raising the prospect that rhIL-7 therapy could enhance T cell reactivity to chronic infection by diminishing the frequency of senescent cells.

As of 2011, at least 15 ongoing studies of rhIL-7 therapy were underway[38]. Investigators are seeking to utilize rhIL-7 to enhance viral clearance in the setting of chronic viral infection, including hepatitis B, hepatitis C and HIV infection. RhIL-7 is being tested for its capacity to augment immune reconstitution following chemotherapy and/or bone marrow transplantation and in the setting of idiopathic CD4+ lymphopenia. Trials have been initiated to test its efficacy as a vaccine adjuvant in aged populations and trials are planned to determine whether rhIL-7 therapy will augment the efficacy of tumor vaccines and adoptive T cell therapy for cancer. Together, the bulk of murine data and the emerging clinical data suggest that the IL-7 may prove clinically useful as a recombinant cytokine for a variety of immune indications, spanning immunodeficiency, chronic viral infection and cancer.

6. IL-7 as a Co-factor in Autoimmunity and Alloimmunity

Over 30 years ago, investigators identified the seemingly paradoxical coexistence of autoimmunity and immunodeficiency by demonstrating autoantibodies in a large proportion of patients with immunodeficiency[39]. It is now widely appreciated that lymphopenia often coexists with human autoimmune disease[40–42], and the hypothesis that lymphopenia predisposes hosts to autoimmunity generated by these correlative studies has been confirmed in murine models ranging from autoimmune colitis, to gastritis to diabetes[43–46]. Given the direct role that IL-7 plays in augmenting reactivity to self-antigens during lymphopenia[26, 29], it is not surprising that IL-7 has emerged as a cofactor in the development of autoimmune disease in general and that elevated IL-7 levels found in lymphopenic hosts could predispose to autoimmunity. Beyond the role that IL-7 is recognized to play in the predisposition to autoimmunity, animal models and human studies also provide evidence for IL-7 in perpetuating autoimmune inflammation. For instance, inflamed joints in rheumatoid arthritis show increased IL-7 production, perhaps as a result of TNF-α and IL-1β induced regulation[47]. Similarly, IL-7 plays a direct role in perpetuating murine colitis[48] and depletion of IL7Rα+ cells can abrogate established disease[49].

6.1 IL7R Polymorphisms and Autoimmunity

Recently, polymorphisms in IL7R, the gene encoding IL7Rα, have been shown to modulate the risk of developing several autoimmune conditions including multiple sclerosis[50, 51], ulcerative colitis[52], sarcoidosis[53] and primary biliary cirrhosis[54]. Some studies suggest a link to type 1 diabetes, but the statistical significance of this association is not strong enough to be definitive in a genome wide study [55, 56]. The risk of developing acute GVHD[57] and the risk of treatment related mortality[58] after allogeneic stem-cell transplantation has also shown some correlation with donor IL7R genotype. While all of these associations show only modest influences on disease susceptibility (RR 1.07–1.37, Table 1), taken together they provide strong evidence for an important role for IL-7 in modulating susceptibility to human autoimmune and potentially alloimmune disease.

Table 1

Several IL7R single nucleotide polymorphisms (SNPs) have been associated with autoimmune conditions in case control genome wide association studies. All associations have low odds ratios and are in strong linkage disequilibrium with the functional SNP rs6897932, suggesting they are due to a common mechanism. Percentages of co-carriage of the studied allele with the MS predisposing allele rs6897932*C and LD scores were calculated based on Hapmap data of a Utah population with northern and western European ancestry (CEU).

DiseaseSNPRisk AlleleOdds Ratio% of haplotypes including risk allele and rs6897932*CLD (D’) with rs6897932
Multiple Sclerosisrs6897932C1.37100%1
Type 1 Diabetesrs6897932C1.07100%1
Primary Biliary Cirrhosisrs860413A1.3398.7%0.93
Ulcerative colitisrs3194051G1.07100%1
Sarcoidosisrs10213865A1.32100%1

In the genetic studies localizing IL7R susceptibility alleles, Single Nucleotide Polymorphisms (SNPs) were utilized to tag for larger genomic regions. This approach is based on the fact that SNP alleles inherited at one locus influence alleles inherited at a proximal locus, a property known as linkage disequilibrium (LD). Knowledge of LD generated through the Hapmap project has been used as the basis for Genome Wide Association studies (GWAS), as it allows a finite number of SNPs to be used as representatives for the entire genome. Which SNP is chosen as a marker for a certain region varies based on the study design and gene chip manufacturer. All of the SNPs in the IL7R region that have been associated with autoimmunity and risk after stem cell transplantation are in strong linkage disequilibrium with rs6897932, a functional SNP located in exon 6 of IL7R. The genotype that is now clearly associated with an increased susceptibility to multiple sclerosis contains a cytosine at rs6897932 (rs6897932*C), whereas a thymine base in the same location is protective (odds ratio ~0.8), and heterozygosity at this allele renders a risk intermediate between the two (odds ratio ~1.0). Rs6897932 is a non-synonymous SNP affecting whether amino acid 244 in IL7Rα is transcribed as a threonine (rs6897932*C genotype) or an isoleucine (rs6897932*T genotype). Amino acid 244 is located in exon 6, at the exact location where splicing of the full-length protein occurs during posttranslational processing and the IL7R genotype impacts the efficiency of exon 6 splicing. As a result, individuals with a CC genotype at Rs6897932 (and thus increased susceptibility to autoimmune disease) show higher levels of the spliced IL7R isoform compared to individuals with a TT genotype. Moreover, individuals with a CC genotype have been reported to have higher levels of circulating IL7Rα, consistent with a model wherein splicing efficiency determines levels of circulating soluble IL7Rα[51, 59, 60].

Despite findings in numerous studies demonstrating modulation of susceptibility to autoimmune disease based upon IL7R polymorphisms, the mechanisms whereby these genetic variations alter risk remain to be elucidated. Most hypotheses rest upon the presumption that modulation in autoimmunity risk is a result of modulation in soluble IL7Rα levels, although this has not been definitively demonstrated. Recent work using a recombinant fusion protein consisting of the IL7Rα extracellular domain linked to a human IgG1 Fc chain showed lowered IL-7 induced STAT5 phosphorylation in human T-cells in vitro in the presence of the fusion protein[61, 62]. The authors suggested that the fusion protein is an accurate mimic of soluble receptor, which if true, would suggest that increased levels of circulating IL7Rα primarily serve to inhibit IL-7 signaling. In order for such a regulator to predispose to autoimmunity, one would have to invoke regulatory effects of IL-7, which have been demonstrated[63], but have not been considered the major effect of IL-7 signaling and occur simultaneously with activating aspects on T cells. An alternative hypothesis is that IL-7 signaling is increased or potentiated in the presence of circulating IL7Rα, similar to the immune potentiating effects of soluble IL15Rα and soluble IL2Rα on cytokine signaling[64, 65].

Given the immune stimulatory properties of IL-7 discussed above, one could easily envision a scenario wherein potentiation of IL-7 signaling could promote increased survival and peripheral expansion of autoreactive T-cell clones leading to increased susceptibility to autoimmune disease. Indeed, recent studies showing potentiation of IL-7 induced antitumor effects when IL-7 is administered as an IL-7:IL7Rα extracellular domain complex are consistent with this model [57]. We await future studies that more clearly delineate the biology of soluble IL7Rα and shed more light on the biology responsible for these intriguing genetic observations. Regardless of the exact biology at play, the fact that the allele associated with increased autoimmunity is a common variant, raises the prospect of hereditary pressure against the opposite, protective allele. It is plausible that genetic mechanisms within the IL7 axis that increase the risk of autoimmunity may have provided an evolutionary benefit in fighting infections or cancer.

6.2 IL-7 in Graft Versus Host Disease

Graft-versus-host disease represents one of the major morbidities complicating hematopoietic stem cell transplantation (HSCT). The alloantigens that drive pathology in this setting are generally stronger stimuli than the self-antigens that drive autoimmune disease, but there is significant overlap between the pathophysiology of GVHD and autoimmunity. Patients undergoing hematopoietic HSCT universally experience lymphopenia and elevated IL-7 levels as part of the procedure, raising the prospect that IL-7 could contribute to morbidity in this setting[19, 66]. Further, murine models demonstrate that IL-7 is required for the development of GVHD[67], that neutralization of IL-7 can prevent GVHD[68] and that administration of rhIL7 lowers increases the risk for developing GVHD[69]. It is perhaps not surprising therefore that those genetic and/or environmental variables, which modulate IL-7 biology, might also modulate risk in this setting. Indeed, the risk of GVHD is increased with higher IL-7 levels post-SCT[70, 71]. Furthermore, some groups have noted that IL7R polymorphisms correlate with the risk of GVHD and treatment related mortality following stem cell transplantation[58, 72], although this has not been confirmed in other studies. Despite that an effect of the exon 6 SNP (rs6897932) was not observed in these studies, the polymorphisms that showed a positive association are in strong LD with rs6897932. Thus, further studies are required to clarify whether sIL7Rα contributes to the risk of GVHD or whether the genetic association observed relate to an entirely different mechanism.

Despite the potential for IL-7 to mediate adverse effects in the setting of GVHD, it is important to note that the potent immunorestorative effects of this agent could also potentially mediate benefit. IL-7 therapy potently augments immune reconstitution in the context of syngeneic or T cell depleted HSCT[73, 74], where GVHD is much less likely and impaired immune reconstitution remains is a major cause of morbidity and mortality. Because of this, a clinical trial is currently underway to determine whether rhIL-7 can augment immune reconstitution and diminish morbidity following stem cell transplantation.

7. IL7R and CRLF2 as Oncogenes

IL7Rα’s involvement in oncogenesis is closely linked to CRLF2 (also known as TSLPR), therefore both receptors will be discussed in this section. Signaling of IL-7 and TSLP is complex and the details continue to be elucidated. Briefly, IL7Rα associates with IL-2Rγ (CD132) to form the IL-7 receptor complex, and IL7Rα associates with CRLF2 to form the thymic stromal lymphopoietin receptor complex. IL7Rα associates with JAK1, IL- 2Rγ associates with JAK3, while CRLF2 associates with JAK2[75]. As a result, IL-7 signals via JAK1 and JAK3 to mediate phosphorylation of STAT1, STAT3 and STAT5, while TSLP signals via JAK1 and JAK2 to phosphorylate STAT5. Given the important roles of IL-7 and TSLP in survival and proliferation of developing B cells and T cells, it is not surprising that the potent growth pathways mediated by signaling through these receptors would be hijacked by malignancies comprising these populations.

7.1 CRLF2 mutations in BCP-ALL

B cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common malignancy of childhood, and results from clonal expansion of early pre-B cells. IL7Rα is constitutively expressed in BCP-ALL cells, as IL7Rα is also expressed on the normal counterpart. IL-7 stimulates proliferation of BCP-ALL leukemia cells in vitro and in vivo, and IL-7 signaling reverses rapamycin induced growth inhibition of BCP-ALL cells[76]. Recently several mutations in TSLP and IL-7 signaling pathways have been discovered in BCP-ALL (Figure 1A). The first to be reported were mutations in JAK1 and JAK2[77–80], with a higher frequency of mutations reported in JAK2, which associates with CRLF2[75]. Subsequently, translocations and mutations in CRLF2 itself were discovered[81–84]. CRLF2 mutations often involved the substitution of a cysteine for a phenylalanine at amino acid 232 (F232C), resulting in constitutive CRLF2 dimerization and cytokine independent growth (Figure 1A, II)[81, 82]. JAK2 and CRLF2 mutations are mutually exclusive, providing evidence for involvement in the same oncogenic pathway[81, 82]. Both F232C CRLF2 mutations and JAK2 mutations are associated with CRLF2 over expression, which can be detected by flow cytometry. In total, CRLF2 is over expressed in approximately 10–15% of adult and pediatric BCP-ALL, with a higher frequency in patients with high-risk disease and in BCP-ALL associated with Down’s syndrome[81, 82]. Because patients with JAK2 and CRLF2 mutations have more aggressive disease and inferior survival, it is possible that screening for this mutation, perhaps via identification of overexpression of CRLF2 expression, could become an important component in assessing prognosis and/or stratifying therapy for BCP-ALL (Figure 1A, I). Moreover, because both groups demonstrate over expression of CRLF2, it is possible that therapies could be developed for these high-risk groups based upon targeting of CRLF2.

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An external file that holds a picture, illustration, etc. Object name is nihms360289f1b.jpg

Figure 1A. BCP-ALL: CRLF2/IL7R axis mutations occurs in 10–15% of cases, is associated with CRLF2 overexpression and a poor prognosis

I. Activating JAK2 mutations are found in approximately 8% and are always associated with over expression of CRLF2.

II. CRLF2 mutations, most commonly F232C or complex insertions and deletions, encode for an unpaired cysteine in the juxtamembrane domain, leading to homodimerization and CRLF2 activation.

III. IL7R S185C mutations found in the juxtamembrane domain (exon 5), are typically associated with overexpression of CRLF2.

IV. IL7R insertion and/or deletion mutations in the transmembrane domain (exon 6) encode for an unpaired cysteine, leading to homodimerization and IL7R activation. In BCP-ALL, this mutation is typically associated with overexpression of CRLF2.

Figure1B: T cell-ALL: IL7R axis mutations occurs in ~25% of cases, is not associated with CRLF2 expression and does not impact on prognosis.

I. Activating JAK1 mutations leading to ligand independent signaling ( ~15% of cases)

II. IL7R mutations in exon 6 encoding for an upaired cysteine leads to homodimerization and ligand-, gc- and CRLF2-independent signaling. (~10%)

7.2 IL7R mutations in B-ALL

In addition to an emerging role for CRLF2 signaling in BCP-ALL pathogenesis, gain of function mutations in IL7R have also recently been found in BCP-ALL[85]. Shochat et al. screened 286 BCP-ALL bone marrow samples for IL7R mutations. Among leukemias with CRLF2 over expression, IL7R mutations were found in 6% vs. 0.6% in those without CRLF2 over expression. Two types of gain-of-function mutations were identified in IL7R. Four patients exhibited substitution of a cysteine for serine at position 185 (S185C) in the juxtamembranous portion of the extracellular domain in exon 5 (Figure 1A, III), while five patients showed of in-frame insertions and/or deletions which included the addition of an unpaired cysteine within the transmembrane domain encoded by exon 6 (Figure 1A, IV). To study the function of the mutated IL7R, the S185C mutant IL7R was introduced into BAF3, an IL-3 dependent mouse pro-B cell line, generating cell lines that expressed wild type or mutant IL7Rα with or without CRLF2. S185C IL7R mediated constitutive, ligand independent activation via homodimerization involving disulfide bonds resulting from cysteine-cysteine interactions. Constitutive activation was abrogated when the cysteine was replaced by a glycine. The addition of a cysteine in the juxtamembranous region of a cytokine receptor as a mechanism for generating constitutive activation has also been observed in CRLF2 (discussed above) as well as other leukemias (e.g. erythropoietin receptor), raising the prospect that this is a common mechanism for mutational activation of receptor tyrosine kinases in leukemia[86, 87].

Interestingly, while nearly all of the BCP-ALL mutations were associated with co-expression of CRLF2, and CRLF2 over expressing BCP-ALL cells continued to respond to TSLP by phosphorylating STAT5, studies thus far do not demonstrate response to exogenous IL-7[88]. Furthermore, Shochat et al found that S185C IL7R mediated cytokine independent growth only when expressed with CRLF2. Thus, IL7R mutations occur in a small fraction of all cases of BCP-ALL, and appear to mediate IL-7 independent signaling. IL7R mutations found in BCP-ALL are typically associated with CRLF2 over expression, which appears to retain the capacity to respond to CRLF2 and likely cooperates with the mutant IL7R in BCP-ALL oncogenesis.

7.3 IL7R mutations in T-ALL

T cell acute lymphoblastic leukemia (T-ALL), a common leukemia of children and young adults, is comprised of clonal IL7Rα cells derived from transformation of triple negative thymocytes. Previous work demonstrating that T-ALL cells respond to IL-7 in vitro[89–91] and JAK1 mutations occur in >15% of cases of adult T-ALL (Figure 1B, I), had implicated the IL7R axis in this disease[92]. Recently, two groups sequenced IL7R genes in several T-ALL cohorts and a found a mutation rate approximating 10%[85, 93]. Similar to the IL7R mutations found in BCP-ALL, nearly all encoded for a mutant, unpaired cysteine in the transmembrane domain of exon 6 (Figure 1B, II). Unlike the results in BCP-ALL however, the vast majority of T-ALL samples were not associated with CRLF2 expression. Furthermore, the T-ALL IL7R gain-of-function mutations were capable of transforming cells, regardless of the presence or absence of CRLF2[85] or IL-2Rγ and JAK3[93]. Consistent with this, mutant IL7R expressing T cells show activation of JAK1 and STAT5, without activation of JAK2 or JAK3. Pharmacological inhibition of the JAK1 and STAT5 induced tumor cell death in vitro and diminished tumor growth rate in vivo, raising the prospect that agents targeting IL7Rα, JAK1 or STAT5 could be used for specific therapy of these tumors[93]. In summary, mutant IL7R is found not uncommonly in T-ALL, where it functions independently of CRLF2 and IL-2Rγ to induce transformation.

8. Conclusion

Since the discovery of IL-7 over 20 years ago, a substantial body of basic research has elucidated fundamental physiologic roles for this cytokine, including non-redundant roles in lymphocyte and lymph node development and peripheral T cell homeostasis. More recently, the IL-7 axis has been implicated in the pathophysiology of a variety of diseases, including effects of germline variation and somatic mutations in IL7Rα in autoimmunity and cancer. This knowledge base paves the way for current and future translational and clinical studies, including clinical trials of rhIL-7 that are currently underway in cancer, HIV, stem cell transplantation and chronic viral infection as well as anticipated studies that seek to inhibit IL7R signaling in the context of cancer and autoimmune disease.

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HIGHLIGHTS

  • In man, IL-7 is essential for T cell development,and contributes to B cell development

  • Human IL-7 is a major modulator of T-cell homeostasis

  • IL7R genotype influences susceptibility to several autoimmune diseases

  • Gain-of-function mutations in IL7R and CRLF2 contribute to oncogenesis in leukemia

  • Clinical trials using rhIL-7 show it to be well tolerated with promising activity

Footnotes

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References

1. Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–655. [Abstract] [Google Scholar]
2. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998;20:394–397. [Abstract] [Google Scholar]
3. Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, et al. The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet. 1993;2:1099–1104. [Abstract] [Google Scholar]
4. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) Nature. 1995;377:65–68. [Abstract] [Google Scholar]
5. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Adams S, Howe SJ, et al. Long-term persistence of a polyclonal T cell repertoire after gene therapy for x-linked severe combined immunodeficiency. Sci Transl Med. 2011;3:97ra79. [Abstract] [Google Scholar]
6. Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. 2000;96:2803–2807. [Abstract] [Google Scholar]
7. Giliani S, Mori L, de Saint Basile G, Le Deist F, Rodriguez-Perez C, Forino C, et al. Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients. Immunol Rev. 2005;203:110–126. [Abstract] [Google Scholar]
8. Grabstein KH, Waldschmidt TJ, Finkelman FD, Hess BW, Alpert AR, Boiani NE, et al. Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody. J Exp Med. 1993;178:257–264. [Europe PMC free article] [Abstract] [Google Scholar]
9. Kikuchi K, Lai AY, Hsu CL, Kondo M. IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF. J Exp Med. 2005;201:1197–1203. [Europe PMC free article] [Abstract] [Google Scholar]
10. Namikawa R, Muench MO, de Vries JE, Roncarolo MG. The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal-cell-independent expansion and differentiation of human fetal pro-B cells in vitro. Blood. 1996;87:1881–1890. [Abstract] [Google Scholar]
11. Dittel BN, LeBien TW. The growth response to IL-7 during normal human B cell ontogeny is restricted to B-lineage cells expressing CD34. J Immunol. 1995;154:58–67. [Abstract] [Google Scholar]
12. Parrish YK, Baez I, Milford TA, Benitez A, Galloway N, Rogerio JW, et al. IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J Immunol. 2009;182:4255–4266. [Europe PMC free article] [Abstract] [Google Scholar]
13. Nodland SE, Berkowska MA, Bajer AA, Shah N, de Ridder D, van Dongen JJ, et al. IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells. Blood. 2011 [Europe PMC free article] [Abstract] [Google Scholar]
14. Malaspina A, Moir S, Chaitt DG, Rehm CA, Kottilil S, Falloon J, et al. Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood. 2007;109:2086–2088. [Europe PMC free article] [Abstract] [Google Scholar]
15. Malaspina A, Moir S, Ho J, Wang W, Howell ML, O'Shea MA, et al. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci U S A. 2006;103:2262–2267. [Europe PMC free article] [Abstract] [Google Scholar]
16. Sportes C, Babb RR, Krumlauf MC, Hakim FT, Steinberg SM, Chow CK, et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin Cancer Res. 2010;16:727–735. [Europe PMC free article] [Abstract] [Google Scholar]
17. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–1711. [Europe PMC free article] [Abstract] [Google Scholar]
18. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–1700. [Europe PMC free article] [Abstract] [Google Scholar]
19. Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, et al. A potential role for interleukin-7 in T-cell homeostasis. Blood. 2001;97:2983–2990. [Abstract] [Google Scholar]
20. Maraskovsky E, Teepe M, Morrissey PJ, Braddy S, Miller RE, Lynch DH, et al. Impaired survival and proliferation in IL-7 receptor-deficient peripheral T cells. J Immunol. 1996;157:5315–5323. [Abstract] [Google Scholar]
21. Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol. 2009;10:66–74. [Abstract] [Google Scholar]
22. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nature medicine. 2011 [Europe PMC free article] [Abstract] [Google Scholar]
23. Mavroukakis SA, Muehlbauer PM, White RL, Jr, Schwartzentruber DJ. Clinical pathways for managing patients receiving interleukin 2. Clin J Oncol Nurs. 2001;5:207–217. [Abstract] [Google Scholar]
24. Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med. 2001;194:1731–1741. [Europe PMC free article] [Abstract] [Google Scholar]
25. Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009;10:149–157. [Europe PMC free article] [Abstract] [Google Scholar]
26. Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000;1:426–432. [Abstract] [Google Scholar]
27. Goldrath AW, Bevan MJ. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity. 1999;11:183–190. [Europe PMC free article] [Abstract] [Google Scholar]
28. Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195:1523–1532. [Europe PMC free article] [Abstract] [Google Scholar]
29. Ernst B, Lee DS, Chang JM, Sprent J, Surh CD. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity. 1999;11:173–181. [Abstract] [Google Scholar]
30. Hodge JN, Srinivasula S, Hu Z, Read SW, Porter BO, Kim I, et al. Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance. Blood. 2011 [Europe PMC free article] [Abstract] [Google Scholar]
31. Dudley ME, Wunderlich J, Nishimura MI, Yu D, Yang JC, Topalian SL, et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma. J Immunother. 2001;24:363–373. [Abstract] [Google Scholar]
32. Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother. 2001;24:287–293. [Abstract] [Google Scholar]
33. Schwartzentruber DJ. High-dose interleukin-2 is an intensive treatment regardless of the venue of administration. Cancer J. 2001;7:103–104. [Abstract] [Google Scholar]
34. Rosenberg SA, Sportes C, Ahmadzadeh M, Fry TJ, Ngo LT, Schwarz SL, et al. IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells. J Immunother. 2006;29:313–319. [Europe PMC free article] [Abstract] [Google Scholar]
35. Sportes C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med. 2008;205:1701–1714. [Europe PMC free article] [Abstract] [Google Scholar]
36. Sereti I, Dunham RM, Spritzler J, Aga E, Proschan MA, Medvik K, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection. Blood. 2009;113:6304–6314. [Europe PMC free article] [Abstract] [Google Scholar]
37. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelievre JD, et al. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest. 2009;119:997–1007. [Europe PMC free article] [Abstract] [Google Scholar]
38. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11:330–342. [Europe PMC free article] [Abstract] [Google Scholar]
39. Ammann AJ, Wara DW, Pillarisetty RJ, Talal N. The prevalence of autoantibodies in T-cell, B-cell, and phagocytic immunodeficiency disorders. Clin Immunol Immunopathol. 1979;14:456–466. [Abstract] [Google Scholar]
40. Dias AM, do Couto MC, Duarte CC, Ines LP, Malcata AB. White blood cell count abnormalities and infections in one-year follow-up of 124 patients with SLE. Ann N Y Acad Sci. 2009;1173:103–107. [Abstract] [Google Scholar]
41. Dhir V, Singh AP, Aggarwal A, Naik S, Misra R. Increased T-lymphocyte apoptosis in lupus correlates with disease activity and may be responsible for reduced T-cell frequency: a cross-sectional and longitudinal study. Lupus. 2009;18:785–791. [Abstract] [Google Scholar]
42. Goeb V, Salle V, Duhaut P, Jouen F, Smail A, Ducroix JP, et al. Clinical significance of autoantibodies recognizing Sjogren's syndrome A (SSA), SSB, calpastatin and alpha-fodrin in primary Sjogren's syndrome. Clin Exp Immunol. 2007;148:281–287. [Abstract] [Google Scholar]
43. King C, Ilic A, Koelsch K, Sarvetnick N. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell. 2004;117:265–277. [Abstract] [Google Scholar]
44. Gleeson PA, Toh BH, van Driel IR. Organ-specific autoimmunity induced by lymphopenia. Immunol Rev. 1996;149:97–125. [Abstract] [Google Scholar]
45. McHugh RS, Shevach EM. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol. 2002;168:5979–5983. [Abstract] [Google Scholar]
46. Krupica T, Jr, Fry TJ, Mackall CL. Autoimmunity during lymphopenia: a two-hit model. Clin Immunol. 2006;120:121–128. [Abstract] [Google Scholar]
47. Ponchel F, Cuthbert RJ, Goëb V. IL-7 and lymphopenia. Clin Chim Acta. 2011;412:7–16. [Abstract] [Google Scholar]
48. Shinohara T, Nemoto Y, Kanai T, Kameyama K, Okamoto R, Tsuchiya K, et al. Upregulated IL-7 receptor alpha expression on colitogenic memory CD4+ T cells may participate in the development and persistence of chronic colitis. J Immunol. 2011;186:2623–2632. [Abstract] [Google Scholar]
49. Yamazaki M, Yajima T, Tanabe M, Fukui K, Okada E, Okamoto R, et al. Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis. J Immunol. 2003;171:1556–1563. [Abstract] [Google Scholar]
50. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallstrom E, Khademi M, et al. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nat Genet. 2007;39:1108–1113. [Abstract] [Google Scholar]
51. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, et al. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat Genet. 2007;39:1083–1091. [Abstract] [Google Scholar]
52. Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–252. [Europe PMC free article] [Abstract] [Google Scholar]
53. Heron M, Grutters JC, van Moorsel CH, Ruven HJ, Huizinga TW, van der Helm-van Mil AH, et al. Variation in IL7R predisposes to sarcoid inflammation. Genes Immun. 2009;10:647–653. [Abstract] [Google Scholar]
54. Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat Genet. 2011 [Europe PMC free article] [Abstract] [Google Scholar]
55. Santiago JL, Alizadeh BZ, Martinez A, Espino L, de la Calle H, Fernandez-Arquero M, et al. Study of the association between the CAPSL-IL7R locus and type 1 diabetes. Diabetologia. 2008;51:1653–1658. [Abstract] [Google Scholar]
56. Todd JA, Walker NM, Cooper JD, Smyth DJ, Downes K, Plagnol V, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet. 2007;39:857–864. [Europe PMC free article] [Abstract] [Google Scholar]
57. Andersson A, Srivastava MK, Harris-White M, Huang M, Zhu L, Elashoff D, et al. Role of CXCR3 ligands in IL-7/IL-7R{alpha}-Fc-mediated antitumor activity in lung cancer. Clin Cancer Res. 2011;17:3660–3672. [Europe PMC free article] [Abstract] [Google Scholar]
58. Andersson A, Yang SC, Huang M, Zhu L, Kar UK, Batra RK, et al. IL-7 promotes CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer. J Immunol. 2009;182:6951–6958. [Abstract] [Google Scholar]
59. Rose T, Lambotte O, Pallier C, Delfraissy JF, Colle JH. Identification and biochemical characterization of human plasma soluble IL-7R: lower concentrations in HIV-1-infected patients. J Immunol. 2009;182:7389–7397. [Abstract] [Google Scholar]
60. Hoe E, McKay FC, Schibeci SD, Gandhi K, Heard RN, Stewart GJ, et al. Functionally significant differences in expression of disease-associated IL-7 receptor alpha haplotypes in CD4 T cells and dendritic cells. J Immunol. 184:2512–2517. [Abstract] [Google Scholar]
61. Maier LM, Anderson DE, Severson CA, Baecher-Allan C, Healy B, Liu DV, et al. Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses. J Immunol. 2009;182:1541–1547. [Europe PMC free article] [Abstract] [Google Scholar]
62. Crawley AM, Faucher S, Angel JB. Soluble IL-7R alpha (sCD127) inhibits IL-7 activity and is increased in HIV infection. J Immunol. 2010;184:4679–4687. [Abstract] [Google Scholar]
63. Guimond M, Veenstra RG, Grindler DJ, Zhang H, Cui Y, Murphy RD, et al. Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol. 2009;10:149–157. [Europe PMC free article] [Abstract] [Google Scholar]
64. Cabrera R, Ararat M, Cao M, Xu Y, Wasserfall C, Atkinson MA, et al. Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25) Dig Dis Sci. 2010;55:484–495. [Europe PMC free article] [Abstract] [Google Scholar]
65. Bulanova E, Budagian V, Duitman E, Orinska Z, Krause H, Rückert R, et al. Soluble Interleukin IL-15Ralpha is generated by alternative splicing or proteolytic cleavage and forms functional complexes with IL-15. J Biol Chem. 2007;282:13167–13179. [Abstract] [Google Scholar]
66. Bolotin E, Annett G, Parkman R, Weinberg K. Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant. 1999;23:783–788. [Abstract] [Google Scholar]
67. Chung B, Dudl E, Toyama A, Barsky L, Weinberg KI. Importance of interleukin-7 in the development of experimental graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:16–27. [Abstract] [Google Scholar]
68. Chung B, Dudl EP, Min D, Barsky L, Smiley N, Weinberg KI. Prevention of graft-versus-host disease by anti IL-7Ralpha antibody. Blood. 2007;110:2803–2810. [Europe PMC free article] [Abstract] [Google Scholar]
69. Sinha ML, Fry TJ, Fowler DH, Miller G, Mackall CL. Interleukin 7 worsens graft-versus-host disease. Blood. 2002;100:2642–2649. [Abstract] [Google Scholar]
70. Dean RM, Fry T, Mackall C, Steinberg SM, Hakim F, Fowler D, et al. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J Clin Oncol. 2008;26:5735–5741. [Europe PMC free article] [Abstract] [Google Scholar]
71. Thiant S, Yakoub-Agha I, Magro L, Trauet J, Coiteux V, Jouet JP, et al. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone marrow transplantation. 2010;45:1546–1552. [Abstract] [Google Scholar]
72. Shamim Z, Ryder LP, Christensen IJ, Toubert A, Norden J, Collin M, et al. Prognostic significance of interleukin-7 receptor-alpha gene polymorphisms in allogeneic stem-cell transplantation: a confirmatory study. Transplantation. 2011;91:731–736. [Abstract] [Google Scholar]
73. Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood. 1996;88:1887–1894. [Abstract] [Google Scholar]
74. Alpdogan O, Schmaltz C, Muriglan SJ, Kappel BJ, Perales MA, Rotolo JA, et al. Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood. 2001;98:2256–2265. [Abstract] [Google Scholar]
75. Rochman Y, Kashyap M, Robinson GW, Sakamoto K, Gomez-Rodriguez J, Wagner KU, et al. Thymic stromal lymphopoietin-mediated STAT5 phosphorylation via kinases JAK1 and JAK2 reveals a key difference from IL-7-induced signaling. Proc Natl Acad Sci U S A. 2010;107:19455–19460. [Europe PMC free article] [Abstract] [Google Scholar]
76. Brown VI, Fang J, Alcorn K, Barr R, Kim JM, Wasserman R, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003;100:15113–15118. [Europe PMC free article] [Abstract] [Google Scholar]
77. Mullighan CG, Zhang J, Harvey RC, Collins-Underwood JR, Schulman BA, Phillips LA, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106:9414–9418. [Europe PMC free article] [Abstract] [Google Scholar]
78. Kearney L, Gonzalez De Castro D, Yeung J, Procter J, Horsley SW, Eguchi-Ishimae M, et al. Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemia. Blood. 2009;113:646–648. [Abstract] [Google Scholar]
79. Gaikwad A, Rye CL, Devidas M, Heerema NA, Carroll AJ, Izraeli S, et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol. 2009;144:930–932. [Europe PMC free article] [Abstract] [Google Scholar]
80. Bercovich D, Ganmore I, Scott LM, Wainreb G, Birger Y, Elimelech A, et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet. 2008;372:1484–1492. [Abstract] [Google Scholar]
81. Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood. 2010;115:1006–1017. [Abstract] [Google Scholar]
82. Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, et al. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2010;107:252–257. [Europe PMC free article] [Abstract] [Google Scholar]
83. Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nat Genet. 2009;41:1243–1246. [Europe PMC free article] [Abstract] [Google Scholar]
84. Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood. 2009;114:2688–2698. [Abstract] [Google Scholar]
85. Shochat C, Tal N, Bandapalli OR, Palmi C, Ganmore I, te Kronnie G, et al. Gain-of-function mutations in interleukin-7 receptor-alpha (IL7R) in childhood acute lymphoblastic leukemias. J Exp Med. 2011;208:901–908. [Europe PMC free article] [Abstract] [Google Scholar]
86. Lu X, Gross AW, Lodish HF. Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J Biol Chem. 2006;281:7002–7011. [Abstract] [Google Scholar]
87. Constantinescu SN, Huang LJ, Nam H, Lodish HF. The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol Cell. 2001;7:377–385. [Abstract] [Google Scholar]
88. Tasian SK, Doral MY, Wood BL, Borowitz MJ, Collins-Underwood JR, Harvey RC, et al. Thymis stromal lymphopoietin stimulation of pediatric acute lymphoblastic leukemias with CRLF2 alterations induces JAK/STAT and PI3K phosphoignaling. Blood. 2010;116:182–183. [Google Scholar]
89. Barata JT, Cardoso AA, Nadler LM, Boussiotis VA. Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1) Blood. 2001;98:1524–1531. [Abstract] [Google Scholar]
90. Barata JT, Keenan TD, Silva A, Nadler LM, Boussiotis VA, Cardoso AA. Common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia. Haematologica. 2004;89:1459–1467. [Abstract] [Google Scholar]
91. Touw I, Pouwels K, van Agthoven T, van Gurp R, Budel L, Hoogerbrugge H, et al. Interleukin-7 is a growth factor of precursor B and T acute lymphoblastic leukemia. Blood. 1990;75:2097–2101. [Abstract] [Google Scholar]
92. Flex E, Petrangeli V, Stella L, Chiaretti S, Hornakova T, Knoops L, et al. Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med. 2008;205:751–758. [Europe PMC free article] [Abstract] [Google Scholar]
93. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011 [Europe PMC free article] [Abstract] [Google Scholar]

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