Stat5-deficient hematopoiesis is permissive for Myc-induced B-cell leukemogenesis.
Despite being an attractive molecular target for both lymphoid and myeloid leukemias characterized by activated tyrosine kinases, the molecular and physiological consequences of reduced signal transducer and activator of transcription-5 (Stat5) during leukemogenesis are not well known. Stat5 is a critical regulator of mouse hematopoietic stem cell (HSC) self-renewal and is essential for normal lymphocyte development. We report that pan-hematopoietic deletion in viable adult Vav1-Cre conditional knockout mice as well as Stat5ab(null/null) fetal liver transplant chimeras generated HSCs with reduced expression of quiescence regulating genes (Tie2, Mpl, Slamf1, Spi1, Cited2) and increased expression of B-cell development genes (Satb1, Dntt, Btla, Flk2). Using a classical murine B-cell acute lymphoblastic leukemia (B-ALL) model, we demonstrate that these HSCs were also poised to produce a burst of B-cell precursors upon expression of Bcl-2 combined with oncogenic Myc. This strong selective advantage for leukemic transformation in the background of Stat5 deficient hematopoiesis was permissive for faster initiation of Myc-induced transformation to B-ALL. However, once established, the B-ALL progression in secondary transplant recipients was Stat5-independent. Overall, these studies suggest that Stat5 can play multiple important roles that not only preserve the HSC compartment but can limit accumulation of potential pre-leukemic lymphoid populations.
Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University, Atlanta GA, USA.
Zhengqi
Z
Wang
Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University, Atlanta GA, USA.
Magdalena
M
Medrzycki
Department of Pathology, Children's Healthcare of Atlanta, Atlanta GA, USA.
Silvia T
ST
Bunting
Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University, Atlanta GA, USA.
Kevin D
KD
Bunting
D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D015448:Leukemia, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors
C489428:Myc protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; C052617:Bcl2 protein, mouse
B-cell transformation; hematopoiesis; leukemogenesis; lymphoid-primed multipotent progenitor; transcription factor