Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis.

Blood
Ki Young ChungMalcolm A S Moore

Abstract

To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (Flt3) receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays, and molecular analyses. In MS-5 stromal cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 14 days. Such W51-associated early CAs disappeared by 4 weeks, yet retained self-renewal properties as demonstrated by generation of secondary and tertiary CAs upon replating. This phenotype appears related to the expression of W51 since it was abolished by exposure to the FLT3 inhibitor, AG1295, but not to the c-kit inhibitor PD16. Wild-type Flt3-overexpressing CD34+ cells exposed to high levels of its physiologic ligand did not produce early CAs, highlighting differences in intracellular signaling between wild-type Flt3 and W51. W51-associated signal transducer and activator of transcription 5 (Stat5) activation plays a major role in this phenotype, although additional downstream targets ...Continue Reading

References

Apr 1, 1994·Leukemia & Lymphoma·F BirgD Birnbaum
Jan 5, 2000·The Journal of Clinical Investigation·D Y JoM A Moore
Nov 25, 2000·British Journal of Haematology·F M Abu-DuhierJ T Reilly
Jul 10, 2001·British Journal of Haematology·F M Abu-DuhierJ T Reilly
Jun 4, 2002·Current Opinion in Hematology·D Gary Gilliland, James D Griffin
Jun 13, 2002·Proceedings of the National Academy of Sciences of the United States of America·Louise M KellyD Gary Gilliland
Aug 15, 2002·Blood·D Gary Gilliland, James D Griffin
Sep 9, 2004·The Journal of Experimental Medicine·Jan Jacob SchuringaMalcolm A S Moore

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Citations

Sep 10, 2008·Molecular and Cellular Biology·Albertus T J WierengaJan Jacob Schuringa
Mar 16, 2007·Blood·Chunaram ChoudharyHubert Serve
Jun 9, 2012·Cancer Cell International·Rosa AyalaFlorinda Gilsanz
Sep 9, 2005·International Journal of Hematology·Chunaram ChoudharyHubert Serve
Feb 24, 2007·Vascular Health and Risk Management·Mitsuko FuruyaHiroshi Ishikura
Sep 25, 2007·Experimental Hematology·Djoke van GosligaJan Jacob Schuringa
Oct 7, 2011·Journal of Molecular Signaling·Jessica A BeachRheem D Medh
Jan 16, 2008·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·M KurahashiS Torihashi
Jan 7, 2009·International Journal of Cancer. Journal International Du Cancer·David C DornMalcolm A S Moore
Jun 21, 2005·Experimental Hematology·Malcolm A S Moore
Oct 5, 2014·Leukemia Research·Ling Li YuanStéphane Manenti
Jan 1, 2012·JAK-STAT·Hein SchepersJan Jacob Schuringa
Oct 27, 2009·Molecular Cell·Chunaram ChoudharyHubert Serve
Aug 21, 2010·Blood·Aleksandra RizoJan Jacob Schuringa
Nov 24, 2005·Hematology·Jonathan D Licht, David W Sternberg
Sep 22, 2006·Human Molecular Genetics·Aleksandra RizoJan Jacob Schuringa
Feb 21, 2014·Oncotarget·Heather M BondGiovanni Morrone
Aug 22, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maria MesuracaGiovanni Morrone

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