STAT5 signaling is required for the efficient induction and maintenance of CML in mice.
The role of signal transducers and activators of transcription 5 (STAT5) in chronic myelogenous leukemia (CML) is controversial. To clarify the role of STAT5 signaling in P210(BCR/ABL) leukemogenesis, P210 was introduced into primary murine STAT5A-deficient (STAT5A(-/-)) bone marrow (BM) cells, which, unlike STAT5A/5B double knockout BM cells, have no major intrinsic hematopoietic defects. Interestingly, only 21% of mice reconstituted with P210-transduced STAT5A(-/-) BM cells developed classic CML, compared with 80% to 100% of P210/STAT5A(+/+) and P210/STAT5A(+/-)-reconstituted animals. The remainder of P210/STAT5A(-/-) animals died from an acute B-cell lymphoblastic leukemia (ALL)-like disease (32%) or a CML/ALL mix (47%), reflecting impairment in the induction and maintenance of CML, which normally predominates in this mouse model. Of mice that ultimately developed CML, P210/STAT5A(-/-) animals had prolonged survival and increased myeloid immaturity. Importantly, reconstitution of wild-type mice with BM cells coexpressing P210 and dominant-negative STAT5 also profoundly reduced the incidence of CML, without impairing the induction of ALL. Altogether, these findings indicate that STAT5 and STAT5A play an important role in the pathogenesis of the CML-like disease in mice. A greater understanding of the STAT5 target genes involved in CML induction may lead to new therapeutic targets that influence CML progenitor cell biology.
Ye
Dan
D
Department of Medicine, University of Texas Southwestern Medical Center, Dallas, USA.
Wolff
Nicholas
N
Li
Li
L
Zhang
Shumin
S
Ilaria
Robert L
RL
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016313:Genes, abl / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
D004791:Enzyme Inhibitors; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse