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Preclinical study demonstrates accelerated Myc-induced leukemogenesis in Stat5-deficient mice, indicating that Stat5 restricts the expansion of pre-leukemic lymphoid progenitors.
// Zhengqi Wang 1 , Magdalena Medrzycki 1 , Silvia T. Bunting 2 , Kevin D. Bunting 1 1 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 2 Department of Pathology, Children's Healthcare of Atlanta, Atlanta GA Correspondence to: Kevin D. Bunting, e-mail: Kevin.bunting@emory.edu Keywords: hematopoiesis, leukemogenesis, lymphoid-primed multipotent progenitor, B-cell transformation, transcription factor Received: July 13, 2015 Accepted: August 12, 2015 Published: August 22, 2015 ABSTRACT 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.
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Wang et al. (2015) studied this question.
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