title: Flt3 does not play a critical role in murine myeloid leukemias induced by MLL fusion genes.
abstract: Leukemias harboring MLL translocations are frequent in children and adults, and respond poorly to therapies. The receptor tyrosine kinase FLT3 is highly expressed in these leukemias. In vitro studies have shown that pediatric MLL-rearranged ALL cells are sensitive to FLT3 inhibitors and clinical trials are ongoing to measure their therapeutic efficacy. We sought to determine the contribution of Flt3 in the pathogenesis of MLL-rearranged leukemias using a myeloid leukemia mouse model. Bone marrow from Flt3 null mice transduced with MLL-ENL or MLL-CBP was transplanted into host mice and Flt3 (-/-) leukemias were compared to their Flt3 wild type counterparts. Flt3 deficiency did not delay disease onset and had minimal impact on leukemia characteristics. To determine the anti-leukemic effect of FLT3 inhibition we studied the sensitivity of MLL-ENL leukemia cells to the FLT3 inhibitor PKC412 ex vivo. As previously reported for human MLL-rearranged leukemias, murine MLL-ENL leukemia cells with higher Flt3 levels were more sensitive to the cytotoxicity of PKC412. Interestingly, Flt3 deficient leukemia samples also displayed some sensitivity to PKC412. Our findings demonstrate that myeloid leukemias induced by MLL-rearranged genes are not dependent upon Flt3 signaling. They also highlight the discrepancy between the sensitivity of cells to Flt3 inhibition in vitro and the lack of contribution of Flt3 to the pathogenesis of MLL-rearranged leukemias in vivo.
authors: Centre National de la Recherche Scientifique, UMR7151, Paris, France.
authors: Stéphanie
authors: S
authors: Albouhair
authors: Ester
authors: E
authors: Morgado
authors: Catherine
authors: C
authors: Lavau
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000172:deficiency / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin
references: Leukemia. 2008 Jan;22(1):66-77
references: 17851551
references: Blood. 1996 Sep 15;88(6):2004-12
references: 8822919
references: Blood. 2004 Jan 1;103(1):267-74
references: 12969963
references: Blood. 2005 Jan 15;105(2):812-20
references: 15374878
references: Cancer Cell. 2003 May;3(5):449-58
references: 12781363
references: EMBO J. 2005 Jan 26;24(2):368-81
references: 15635450
references: Blood. 2007 May 1;109(9):4020-2
references: 17202314
references: Mol Cell Biol. 2006 May;26(10):3902-16
references: 16648484
references: EMBO J. 2000 Sep 1;19(17):4655-64
references: 10970858
references: EMBO J. 1997 Jul 16;16(14):4226-37
references: 9250666
references: Leukemia. 2005 Jun;19(6):953-64
references: 15815718
references: Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19069-74
references: 16354839
references: Int J Hematol. 2003 Dec;78(5):390-401
references: 14704031
references: Cancer Cell. 2002 Mar;1(2):133-43
references: 12086872
references: Cancer Cell. 2012 Oct 16;22(4):524-35
references: 23079661
references: Blood. 2006 Nov 15;108(10):3477-83
references: 16857987
references: Immunity. 1995 Jul;3(1):147-61
references: 7621074
references: Cancer Res. 2005 Dec 15;65(24):11367-74
references: 16357144
references: Blood. 2004 Dec 1;104(12):3679-87
references: 15226186
references: Nat Genet. 2002 Jan;30(1):41-7
references: 11731795
references: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10984-9
references: 10995463
references: Blood. 2005 Oct 1;106(7):2484-90
references: 15956279
references: Br J Haematol. 2010 Nov;151(4):295-311
references: 20813012
references: Blood. 2010 Dec 9;116(24):5089-102
references: 20705759
references: Genes Chromosomes Cancer. 2006 Sep;45(9):846-55
references: 16804919
references: Cancer Res. 2003 Aug 15;63(16):4882-7
references: 12941810
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7853-8
references: 12782787
references: Cancer Cell. 2003 Feb;3(2):173-83
references: 12620411