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Diamond Blackfan anemia is mediated by hyperactive Nemo-like kinase
M C Wilkes1, K Siva2, J Chen2
1Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA.
Nature Communications
|July 5, 2020
Summary
Diamond Blackfan Anemia (DBA), a bone marrow failure syndrome, may be treatable by targeting Nemo-like kinase (NLK). Inhibiting NLK boosts red blood cell production in DBA models and patient cells.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Diamond Blackfan Anemia (DBA) is a rare congenital bone marrow failure syndrome.
- DBA results from ribosomal gene mutations causing ribosomal insufficiency.
- Current DBA treatments have significant associated morbidity.
Purpose of the Study:
- To identify novel therapeutic targets for Diamond Blackfan Anemia.
- To investigate Nemo-like kinase (NLK) as a potential therapeutic target for DBA.
Main Methods:
- Screening for small molecules that enhance erythroid expansion in DBA mouse models.
- Utilizing chemical and genetic inhibition of NLK in mouse and human hematopoietic progenitor cells.
- Analyzing NLK activation at different differentiation stages in DBA models and patient samples.
Main Results:
- A screen identified a compound that inhibits NLK, leading to increased erythroid expansion.
- NLK inhibition effectively increased erythroid expansion in DBA mouse models and human progenitors, including DBA patient bone marrow cells.
- Aberrant NLK activation in DBA was specifically observed at the Megakaryocyte/Erythroid Progenitor (MEP) stage.
Conclusions:
- Nemo-like kinase (NLK) plays a role in mediating aberrant erythropoiesis in Diamond Blackfan Anemia.
- NLK is a promising therapeutic target for developing new treatments for DBA.
- Targeting NLK could improve red blood cell production in DBA patients.
