KIT with D816 Mutations Cooperates with CBFB-MYH11 for Leukemogenesis in Mice

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2011 Dec 14

PMID 22160378

Citations 27

Authors

Ling Zhao

Jan J Melenhorst

Lemlem Alemu

Martha Kirby

Stacie Anderson

Maggie Kench

Shelley Hoogstraten-Miller

Lauren Brinster

Yasuhiko Kamikubo

D Gary Gilliland

P Paul Liu

Affiliations

Soon will be listed here.

Abstract

KIT mutations are the most common secondary mutations in inv(16) acute myeloid leukemia (AML) patients and are associated with poor prognosis. It is therefore important to verify that KIT mutations cooperate with CBFB-MYH11, the fusion gene generated by inv(16), for leukemogenesis. Here, we transduced wild-type and conditional Cbfb-MYH11 knockin (KI) mouse bone marrow (BM) cells with KIT D816V/Y mutations. KIT transduction caused massive BM Lin(-) cell death and fewer colonies in culture that were less severe in the KI cells. D816Y KIT but not wild-type KIT enhanced proliferation in Lin(-) cells and led to more mixed lineage colonies from transduced KI BM cells. Importantly, 60% and 80% of mice transplanted with KI BM cells expressing D816V or D816Y KIT, respectively, died from leukemia within 9 months, whereas no control mice died. Results from limiting dilution transplantations indicate higher frequencies of leukemia-initiating cells in the leukemia expressing mutated KIT. Signaling pathway analysis revealed that p44/42 MAPK and Stat3, but not AKT and Stat5, were strongly phosphorylated in the leukemia cells. Finally, leukemia cells carrying KIT D816 mutations were sensitive to the kinase inhibitor PKC412. Our data provide clear evidence for cooperation between mutated KIT and CBFB-MYH11 during leukemogenesis.

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References

Muller A, Duque J, Shizuru J, Lubbert M . Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene. 2008; 27(44):5759-73. DOI: 10.1038/onc.2008.196. View

Cairoli R, Beghini A, Morello E, Grillo G, Montillo M, Larizza L . Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations. A report of three cases. Leuk Res. 2005; 29(4):397-400. DOI: 10.1016/j.leukres.2004.10.005. View

Valk P, Bowen D, Frew M, Goodeve A, Lowenberg B, Reilly J . Second hit mutations in the RTK/RAS signaling pathway in acute myeloid leukemia with inv(16). Haematologica. 2004; 89(1):106. View

Spritz R, Giebel L, Holmes S . Dominant negative and loss of function mutations of the c-kit (mast/stem cell growth factor receptor) proto-oncogene in human piebaldism. Am J Hum Genet. 1992; 50(2):261-9. PMC: 1682440. View

Dunphy C . Comprehensive review of adult acute myelogenous leukemia: cytomorphological, enzyme cytochemical, flow cytometric immunophenotypic, and cytogenetic findings. J Clin Lab Anal. 1999; 13(1):19-26. PMC: 6807799. DOI: 10.1002/(sici)1098-2825(1999)13:1<19::aid-jcla4>3.0.co;2-1. View

Wang Y, Zhao L, Wu C, Liu P, Shi L, Liang Y . C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci U S A. 2011; 108(6):2450-5. PMC: 3038718. DOI: 10.1073/pnas.1019625108. View

Care R, Valk P, Goodeve A, Abu-Duhier F, Geertsma-Kleinekoort W, Wilson G . Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol. 2003; 121(5):775-7. DOI: 10.1046/j.1365-2141.2003.04362.x. View

Kita K, Shirakawa S, Kamada N . Cellular characteristics of acute myeloblastic leukemia associated with t(8;21)(q22;q22). The Japanese Cooperative Group of Leukemia/Lymphoma. Leuk Lymphoma. 1994; 13(3-4):229-34. DOI: 10.3109/10428199409056286. View

Jiao B, Wu C, Liang Y, Chen H, Xiong S, Chen B . AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia. 2009; 23(9):1598-604. DOI: 10.1038/leu.2009.104. View

10.

Markowitz D, Goff S, Bank A . Safe and efficient ecotropic and amphotropic packaging lines for use in gene transfer experiments. Trans Assoc Am Physicians. 1988; 101:212-8. View

11.

Gleixner K, Mayerhofer M, Aichberger K, Derdak S, Sonneck K, Bohm A . PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2005; 107(2):752-9. DOI: 10.1182/blood-2005-07-3022. View

12.

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S . Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. DOI: 10.1126/science.279.5350.577. View

13.

Masson K, Ronnstrand L . Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3. Cell Signal. 2009; 21(12):1717-26. DOI: 10.1016/j.cellsig.2009.06.002. View

14.

Pedersen M, Ronnstrand L, Sun J . The c-Kit/D816V mutation eliminates the differences in signal transduction and biological responses between two isoforms of c-Kit. Cell Signal. 2008; 21(3):413-8. DOI: 10.1016/j.cellsig.2008.11.008. View

15.

Gallardo H, Tan C, Ory D, Sadelain M . Recombinant retroviruses pseudotyped with the vesicular stomatitis virus G glycoprotein mediate both stable gene transfer and pseudotransduction in human peripheral blood lymphocytes. Blood. 1997; 90(3):952-7. View

16.

Shih L, Liang D, Huang C, Chang Y, Lai C, Lin T . Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2007; 22(2):303-7. DOI: 10.1038/sj.leu.2404995. View

17.

Yaren A, Oztop I, Kargi A, Ulukus C, Onen A, Sanli A . Bax, bcl-2 and c-kit expression in non-small-cell lung cancer and their effects on prognosis. Int J Clin Pract. 2006; 60(6):675-82. DOI: 10.1111/j.1368-5031.2006.00742.x. View

18.

Goemans B, Zwaan C, Cloos J, De Lange D, Loonen A, Reinhardt D . FLT3 and KIT mutated pediatric acute myeloid leukemia (AML) samples are sensitive in vitro to the tyrosine kinase inhibitor SU11657. Leuk Res. 2010; 34(10):1302-7. DOI: 10.1016/j.leukres.2010.04.004. View

19.

Levina V, Marrangoni A, Wang T, Parikh S, Su Y, Herberman R . Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res. 2009; 70(1):338-46. PMC: 4572892. DOI: 10.1158/0008-5472.CAN-09-1102. View

20.

Kuo Y, Landrette S, Heilman S, Perrat P, Garrett L, Liu P . Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell. 2006; 9(1):57-68. DOI: 10.1016/j.ccr.2005.12.014. View