The Blk pathway functions as a tumor suppressor in chronic myeloid leukemia stem cells.
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.
Department of Medicine, Division of Hematology/Oncology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Haojian
H
Zhang
Cong
C
Peng
Yiguo
Y
Hu
Huawei
H
Li
Zhi
Z
Sheng
Yaoyu
Y
Chen
Con
C
Sullivan
Jan
J
Cerny
Lloyd
L
Hutchinson
Anne
A
Higgins
Patricia
P
Miron
Xueqing
X
Zhang
Michael A
MA
Brehm
Dongguang
D
Li
Michael R
MR
Green
Shaoguang
S
Li
D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D016313:Genes, abl; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
C489921:Ebf1 protein, mouse; C489428:Myc protein, mouse; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases