C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice.
The full-length AML1-ETO (AE) fusion gene resulting from t(8;21)(q22;q22) in human acute myeloid leukemia (AML) is not sufficient to induce leukemia in animals, suggesting that additional mutations are required for leukemogenesis. We and others have identified activating mutations of C-KIT in nearly half of patients with t(8;21) AML. To test the hypothesis that activating C-KIT mutations cooperate with AE to cause overt AML, we generated a murine transduction and transplantation model with both mutated C-KIT and AE. To overcome the intracellular transport block of human C-KIT in murine cells, we engineered hybrid C-KIT (HyC-KIT) by fusing the extracellular and transmembrane domains of the murine c-Kit in-frame to the intracellular signaling domain of human C-KIT. We showed that tyrosine kinase domain mutants HyC-KIT N822K and D816V, as well as juxtamembrane mutants HyC-KIT 571+14 and 557-558Del, could transform murine 32D cells to cytokine-independent growth. The protein tyrosine kinase inhibitor dasatinib inhibited the proliferation of 32D cells expressing these C-KIT mutants, with potency in the low nanomolar range. In mice, HyC-KIT N822K induced a myeloproliferative disease, whereas HyC-KIT 571+14 induces both myeloproliferative disease and lymphocytic leukemia. Interestingly, coexpression of AE and HyC-KIT N822K led to fatal AML. Our data have further enriched the two-hit model that abnormalities of both transcription factor and membrane/cytosolic signaling molecule are required in AML pathogenesis. Furthermore, dasatinib prolonged lifespan of mice bearing AE and HyC-KIT N822K-coexpressing leukemic cells and exerted synergic effects while combined with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Yue-Ying
YY
Wang
Li-Juan
LJ
Zhao
Chuan-Feng
CF
Wu
Ping
P
Liu
Lin
L
Shi
Yang
Y
Liang
Shu-Min
SM
Xiong
Jian-Qing
JQ
Mi
Zhu
Z
Chen
Ruibao
R
Ren
Sai-Juan
SJ
Chen
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014178:Translocation, Genetic / Q000235:genetics
C107844:AML1-ETO fusion protein, human; D000964:Antimetabolites, Antineoplastic; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D003561:Cytarabine; D019009:Proto-Oncogene Proteins c-kit
Blood. 2006 Oct 1;108(7):2349-57
16763213
Leukemia. 2006 Jun;20(6):965-70
16598313
Blood. 2006 May 1;107(9):3463-8
16384925
Leukemia. 2008 May;22(5):915-31
18288131
Blood. 1998 Nov 15;92(10):3829-40
9808576
Leukemia. 2009 Sep;23(9):1598-604
19458628
Blood. 2000 Sep 15;96(6):2108-15
10979955
Nat Genet. 1997 Mar;15(3):303-6
9054947
Leukemia. 2005 Sep;19(9):1536-42
16015387
Science. 1998 Jan 23;279(5350):577-80
9438854
Science. 2000 Sep 15;289(5486):1938-42
10988075
Leukemia. 2000 Mar;14(3):513-7
10720153
Cancer Cell. 2002 Jun;1(5):417-20
12124171
Oncogene. 2004 May 24;23(24):4255-62
15156181
J Mol Graph Model. 2004 Oct;23(2):139-52
15363456
J Biol Chem. 2004 Jul 23;279(30):31655-63
15123710
Science. 2004 Jul 16;305(5682):399-401
15256671
Mol Cell Biol. 1993 Apr;13(4):2224-34
7681144
Mol Cell Biol. 2002 Aug;22(15):5506-17
12101243
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9506-11
12881486
Nat Genet. 1996 Mar;12(3):312-4
8589724
J Clin Invest. 2005 Aug;115(8):2159-68
16025155
Mol Cell Biol. 2007 Jan;27(1):267-82
17060458
Blood. 2002 Mar 1;99(5):1741-4
11861291
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10398-403
11526243
Cancer Res. 2006 Jan 1;66(1):473-81
16397263
Int J Oncol. 2009 Jun;34(6):1521-31
19424569
Haematologica. 2004 Aug;89(8):920-5
15339674
Hematology Am Soc Hematol Educ Program. 2004;:80-97
15561678
Nat Med. 2006 Aug;12(8):945-9
16892037
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1104-9
15650049
Mol Cell Biol. 1999 Oct;19(10):6918-28
10490629
World J Gastroenterol. 2008 Mar 28;14(12):1891-7
18350628
Science. 1997 Nov 7;278(5340):1059-64
9353180
Cancer Cell. 2002 Feb;1(1):63-74
12086889