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 and K. M. Sakamoto ()
Additional contact information
M. C. Wilkes: Stanford University
K. Siva: Lund Stem Cell Center, Lund University
J. Chen: Lund Stem Cell Center, Lund University
G. Varetti: Institute for Research in Biomedicine (IRB Barcelona)
M. Y. Youn: Stanford University
H. Chae: Stanford University
F. Ek: Lund University
R. Olsson: Lund University
T. Lundbäck: Karolinska Institutet
D. P. Dever: Stanford University
T. Nishimura: Stanford University School of Medicine
A. Narla: Stanford University
B. Glader: Stanford University
H. Nakauchi: Stanford University School of Medicine
M. H. Porteus: Stanford University
C. E. Repellin: SRI International
H. T. Gazda: Broad Institute of MIT and Harvard
S. Lin: University of California
M. Serrano: Institute for Research in Biomedicine (IRB Barcelona)
J. Flygare: Lund Stem Cell Center, Lund University
K. M. Sakamoto: Stanford University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17100-z

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