Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

M C Wilkes; K Siva; J Chen; G Varetti; M Y Youn; H Chae; F Ek; R Olsson; T Lundbäck; D P Dever; T Nishimura; A Narla; B Glader; H Nakauchi; M H Porteus; C E Repellin; H T Gazda; S Lin; M Serrano; J Flygare; K M Sakamoto

doi:10.1038/s41467-020-17100-z

Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase

Nat Commun. 2020 Jul 3;11(1):3344. doi: 10.1038/s41467-020-17100-z.

Authors

M C Wilkes¹, K Siva², J Chen², G Varetti^{3

4

5}, M Y Youn¹, H Chae¹, F Ek⁶, R Olsson⁶, T Lundbäck⁷, D P Dever⁸, T Nishimura⁹, A Narla¹, B Glader¹, H Nakauchi^{9

10}, M H Porteus⁸, C E Repellin¹¹, H T Gazda^{12

13}, S Lin¹⁴, M Serrano^{3

4

5}, J Flygare², K M Sakamoto¹⁵

Affiliations

¹ Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
² Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, 22184, Sweden.
³ Institute for Research in Biomedicine (IRB Barcelona), Barcelona, 08028, Spain.
⁴ Barcelona Institute of Science and Technology (BIST), Barcelona, 08028, Spain.
⁵ Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, 08028, Spain.
⁶ Chemical Biology and Therapeutics Group, Department of Medical Science, Lund University, Lund, 22184, Sweden.
⁷ Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Department for Medical Biochemistry and Biophysics, Karolinska Institutet, 17177, Stockholm, Sweden.
⁸ Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
⁹ Department of Genetics, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹⁰ Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
¹¹ Biosciences Division, SRI International, Menlo Park, CA, 94025, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹³ Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹⁴ Department of Molecular, Cell and Development Biology, University of California, Los Angeles, CA, 90095, USA.
¹⁵ Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA. [email protected].

Abstract

Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome associated with ribosomal gene mutations that lead to ribosomal insufficiency. DBA is characterized by anemia, congenital anomalies, and cancer predisposition. Treatment for DBA is associated with significant morbidity. Here, we report the identification of Nemo-like kinase (NLK) as a potential target for DBA therapy. To identify new DBA targets, we screen for small molecules that increase erythroid expansion in mouse models of DBA. This screen identified a compound that inhibits NLK. Chemical and genetic inhibition of NLK increases erythroid expansion in mouse and human progenitors, including bone marrow cells from DBA patients. In DBA models and patient samples, aberrant NLK activation is initiated at the Megakaryocyte/Erythroid Progenitor (MEP) stage of differentiation and is not observed in non-erythroid hematopoietic lineages or healthy erythroblasts. We propose that NLK mediates aberrant erythropoiesis in DBA and is a potential target for therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anemia, Diamond-Blackfan / diet therapy
Anemia, Diamond-Blackfan / genetics
Anemia, Diamond-Blackfan / pathology*
Animals
Benzamides / pharmacology
Benzamides / therapeutic use
Cell Differentiation / drug effects
Cell Proliferation
Cells, Cultured
Dioxoles / pharmacology
Dioxoles / therapeutic use
Disease Models, Animal
Erythropoiesis / drug effects
Erythropoiesis / genetics
Hematopoietic Stem Cells / pathology*
Humans
Mice
Mice, Transgenic
Mutation
Primary Cell Culture
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Pyrazoles / pharmacology
Pyrazoles / therapeutic use
Quinolines / pharmacology
Quinolines / therapeutic use
RNA, Small Interfering / metabolism
Ribosomal Proteins / genetics

Substances

4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
Benzamides
Dioxoles
Protein Kinase Inhibitors
Pyrazoles
Quinolines
RNA, Small Interfering
Ribosomal Proteins
Rps19 protein, mouse
LY-2157299
NLK protein, human
Nlk protein, mouse
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding