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Author Notes:

Correspondence to: Kevin D. Bunting, e-mail: Kevin.bunting@emory.edu

We thank Fang Xu for providing help with statistical analyses. EML cells were a gift from Dr. Schickwann Tsai (University of Utah).

We also thank the Emory + Children’s Pediatric Center for support through the Flow cytometry core.

The authors have no competing financial interests to disclose.

Subjects:

Research Funding:

This work was supported by NIH R01DK059380 (K.D. Bunting), the Cure Childhood Cancer Foundation (K.D. Bunting, Z. Wang), and the Aflac Cancer and Blood Disorders Center.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Cell Biology
  • hematopoiesis
  • leukemogenesis
  • lymphoid-primed multipotent progenitor
  • B-cell transformation
  • transcription factor
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • CHRONIC MYELOID-LEUKEMIA
  • SELF-RENEWAL CAPACITY
  • STEM-CELLS
  • BONE-MARROW
  • STEM/PROGENITOR CELLS
  • SIGNAL TRANSDUCER
  • PROGENITOR CELLS
  • IN-VIVO
  • STAT5

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

Tools:

Journal Title:

Oncotarget

Volume:

Volume 6, Number 30

Publisher:

, Pages 28961-28972

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2015 Wang et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

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