title: Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.
abstract: PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: L
authors: L
authors: Chen
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: W
authors: W
authors: Chen
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: M
authors: M
authors: Mysliwski
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: J
authors: J
authors: Serio
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: J
authors: J
authors: Ropa
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors: F A
authors: FA
authors: Abulwerdi
authors: 1] Herman B Wells Center for Pediatric Research, Department of Medical and Molecular Genetics, University School of Medicine, Indianapolis, IN, USA [2] Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: R J
authors: RJ
authors: Chan
authors: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: J P
authors: JP
authors: Patel
authors: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: M S
authors: MS
authors: Tallman
authors: Montefiore Medical Center-North Division, Immunology Laboratory, Cancer Center, Bronx, NY, USA.
authors: E
authors: E
authors: Paietta
authors: 1] Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA [2] Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA.
authors: A
authors: A
authors: Melnick
authors: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: R L
authors: RL
authors: Levine
authors: Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: O
authors: O
authors: Abdel-Wahab
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Z
authors: Z
authors: Nikolovska-Coleska
authors: 1] Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA [2] Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: A G
authors: AG
authors: Muntean
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D049109:Cell Proliferation; D017326:Clinical Trials, Phase III as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D007377:Interleukin-3; C551356:MLL-AF9 fusion protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
references: Structure. 1998 Mar 15;6(3):249-54
references: 9551546
references: Hum Mol Genet. 2007 Jan 1;16(1):92-106
references: 17135274
references: Blood. 1998 Nov 1;92(9):3226-39
references: 9787159
references: EMBO J. 1999 Jul 1;18(13):3564-74
references: 10393173
references: Cancer Cell. 2005 Feb;7(2):179-91
references: 15710330
references: J Clin Invest. 2005 Apr;115(4):919-29
references: 15761502
references: Blood. 2005 May 1;105(9):3737-42
references: 15644411
references: Blood. 2005 Jul 1;106(1):311-7
references: 15761018
references: Blood. 2011 Aug 11;118(6):1504-15
references: 21670473
references: J Exp Med. 2011 Sep 26;208(10):1977-88
references: 21930766
references: Cancer Cell. 2011 Nov 15;20(5):563-75
references: 22094252
references: Genes Dev. 2012 Jan 15;26(2):120-5
references: 22279045
references: N Engl J Med. 2012 Mar 22;366(12):1079-89
references: 22417203
references: Genes Dev. 2012 Jul 15;26(14):1587-601
references: 22759635
references: Cell. 2012 Jul 20;150(2):264-78
references: 22817890
references: Blood. 2005 Nov 1;106(9):3142-9
references: 16030196
references: J Med Chem. 2014 May 22;57(10):4111-33
references: 24749893
references: Curr Opin Genet Dev. 2007 Feb;17(1):23-30
references: 17227708
references: Nature. 2007 Apr 12;446(7137):758-64
references: 17344859
references: Genes Chromosomes Cancer. 2008 Jan;47(1):26-33
references: 17910045
references: Leukemia. 2008 Jan;22(1):66-77
references: 17851551
references: Cancer Metastasis Rev. 2008 Jun;27(2):179-92
references: 18286234
references: Cancer Res. 2008 May 1;68(9):3421-8
references: 18451170
references: Blood. 2008 Dec 1;112(12):4690-3
references: 18796627
references: Blood. 2009 Jan 29;113(5):1086-96
references: 18952898
references: Blood. 2009 Apr 30;113(18):4414-24
references: 19179468
references: J Immunol Methods. 2009 Aug 15;347(1-2):70-8
references: 19567251
references: N Engl J Med. 2009 Sep 24;361(13):1249-59
references: 19776406
references: Nat Biotechnol. 2009 Nov;27(11):1025-31
references: 19881494
references: Cancer Cell. 2010 Feb 17;17(2):198-212
references: 20153263
references: Mol Cell. 2010 Feb 12;37(3):429-37
references: 20159561
references: Blood. 2010 Sep 2;116(9):1433-42
references: 20525924
references: Blood. 2010 Nov 4;116(18):3611-21
references: 20651068
references: Nat Biotechnol. 2011 Jan;29(1):79-83
references: 21131983
references: Blood. 2011 Apr 21;117(16):4253-61
references: 21398220
references: Blood. 2011 May 19;117(20):5350-61
references: 21450902
references: Leukemia. 2011 Aug;25(8):1239-48
references: 21566656
references: Blood. 1999 Dec 1;94(11):3707-16
references: 10572083
references: Nucleic Acids Res. 2000 Jan 1;28(1):349-51
references: 10592271
references: Nat Genet. 2001 Dec;29(4):465-8
references: 11704759
references: Nat Genet. 2002 Jan;30(1):41-7
references: 11731795
references: Blood. 2002 Sep 1;100(5):1532-42
references: 12176867
references: Nat Genet. 2003 Jun;34(2):148-50
references: 12717436
references: Trends Biochem Sci. 2003 Jun;28(6):284-93
references: 12826400
references: Blood. 2004 Jul 15;104(2):307-13
references: 14982869
references: Blood. 1994 Jul 15;84(2):570-3
references: 8025282
references: Nature. 1996 Aug 8;382(6591):541-4
references: 8700228
references: EMBO J. 1997 Jul 16;16(14):4226-37
references: 9250666
references: Cell. 1998 Feb 20;92(4):441-50
references: 9491886
references: BMC Genomics. 2012;13:500
references: 22994565
references: Leukemia. 2013 Feb;27(2):398-408
references: 23103841
references: J Biol Chem. 2013 Apr 12;288(15):10472-82
references: 23457302
references: Blood. 2013 Sep 12;122(11):1914-22
references: 23900238
references: Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):261-6
references: 24363325
references: Nature. 2014 Jan 23;505(7484):495-501
references: 24390350
references: Mol Cancer Ther. 2014 Mar;13(3):565-75
references: 24019208
references: Int J Biochem Cell Biol. 1998 May;30(5):559-66
references: 9693956