The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells
Program in Gene Function and Expression; Department of Medicine, Division of Hematology and Oncology; Program in Molecular Medicine; Department of Pathology; Department of Pediatrics
Medical Subject Headings
Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplastic Stem Cells; Genes, Tumor Suppressor
Cancer Biology | Genetics and Genomics
A therapeutic strategy for treating cancer is to target and eradicate cancer stem cells (CSCs) without harming their normal stem cell counterparts. The success of this approach relies on the identification of molecular pathways that selectively regulate CSC function. Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for CSCs, we show that BCR-ABL downregulates the Blk gene (encoding B-lymphoid kinase) through c-Myc in leukemic stem cells (LSCs) in CML mice and that Blk functions as a tumor suppressor in LSCs but does not affect normal hematopoietic stem cells (HSCs) or hematopoiesis. Blk suppresses LSC function through a pathway involving an upstream regulator, Pax5, and a downstream effector, p27. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. Blk also suppresses the proliferation of human CML stem cells. Our results show the feasibility of selectively targeting LSCs, an approach that should be applicable to other cancers.
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Citation: Nat Genet. 2012 Jul 15;44(8):861-71. doi: 10.1038/ng.2350. Link to article on publisher's site