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

Oncotarget
Zhengqi WangKevin D Bunting

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 recipien...Continue Reading

References

May 9, 2007·Frontiers in Bioscience : a Journal and Virtual Library·Kevin D Bunting
May 15, 2008·Developmental Cell·Keith OrfordDavid T Scadden
May 22, 2008·Nucleic Acids Research·Beth BashamAnne Rascle
Mar 5, 2010·EMBO Molecular Medicine·Andrea HoelblVeronika Sexl
Mar 9, 2010·Cell Stem Cell·Grant A ChallenMargaret A Goodell
Mar 17, 2010·Current Opinion in Immunology·Stephen MalinMeinrad Busslinger
Mar 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Isabel BeermanDerrick J Rossi
Apr 28, 2010·The Journal of Experimental Medicine·Yohei MoritaHiromitsu Nakauchi
Jun 2, 2010·The Journal of Experimental Medicine·Hanno Hock
Oct 28, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Katrin FriedbichlerRichard Moriggl
Mar 16, 2012·The New England Journal of Medicine·Matthew J WalterTimothy A Graubert
Jan 7, 2014·Cell Stem Cell·Peter van GalenJohn E Dick
May 20, 2015·Nature Immunology·Srividya SwaminathanMarkus Müschen

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Citations

May 22, 2019·Stem Cell Research & Therapy·Stefania TrinoLuciana De Luca
Jan 23, 2020·Cancers·Marie Brachet-BotineauFabrice Gouilleux
May 12, 2017·The Journal of Experimental Medicine·Samuel TaylorShoba Amarnath

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Methods Mentioned

BETA
flow cytometry
PCR
immunoprecipitation
transgenic
ChIP
ChIP-seq

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