Oncotarget

Research Papers:

Stat5-deficient hematopoiesis is permissive for Myc-induced B-cell leukemogenesis

Zhengqi Wang, Magdalena Medrzycki, Silvia T. Bunting and Kevin D. Bunting _

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Oncotarget. 2015; 6:28961-28972. https://doi.org/10.18632/oncotarget.5009

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Abstract

Zhengqi Wang1, Magdalena Medrzycki1, Silvia T. Bunting2, Kevin D. Bunting1

1Department of Pediatrics, Division of Hematology-Oncology-BMT, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University, Atlanta GA

2Department 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 Stat5abnull/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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