BLK suppresses CML growth by negatively regulating leukemic stem cell function.
Major finding: BLK suppresses CML growth by negatively regulating leukemic stem cell function.
Mechanism: BLK inhibits leukemic stem cell proliferation via p27 but does not affect normal stem cells.
Impact: Targeting of CSC-specific pathways may promote eradication of these cells in tumors.
Cancer stem cells (CSC) have been proposed to play a key role in tumor initiation, particularly in hematopoietic cancers. However, most antitumor therapies do not efficiently kill these cells, allowing for persistence of CSCs that may contribute to tumor relapse. Therefore, it is important to identify strategies that specifically target CSCs without harming normal stem cells. Using BCR-ABL–induced chronic myeloid leukemia (CML) as a model, Zhang and colleagues identified B-lymphoid kinase (BLK) as a critical regulator of leukemic stem cells (LSC). Downregulation of Blk in BCR-ABL–expressing LSCs was mediated by c-MYC repression of the transcription factor, Pax5, which stimulates Blk expression. Blk deficiency accelerated CML development, whereas Blk overexpression enhanced the survival of CML mice, suggesting that BLK functions as a tumor suppressor in CML. Moreover, Blk expression synergized with BCR-ABL kinase inhibition to eliminate leukemia cells and further increase survival. Blk overexpression diminished the number of LSCs in CML mice, in part due to decreased proliferation and increased apoptosis. In contrast, manipulation of Blk expression did not affect the growth of normal hematopoietic stem cells or their function in colony formation and competitive repopulation assays, indicating that BLK specifically regulates LSCs. The suppressive effect of BLK in LSCs did not require BLK kinase activity but was dependent on induction of the cyclin-dependent kinase inhibitor p27, as survival of CML was significantly reduced in the absence of p27 expression. Importantly, BLK levels were lower in cells derived from patients with CML, and expression of BLK inhibited the proliferation and colony-forming ability of human CML stem cells. These results implicate BLK as an important regulator of LSCs and suggest that targeting of this pathway may allow for selective eradication of cancer stem cells in CML.