Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models Authors
First Online: 22 December 2011 Received: 09 October 2011 Revised: 06 December 2011 Accepted: 07 December 2011 DOI:
Cite this article as: Doki, N., Kitaura, J., Uchida, T. et al. Int J Hematol (2012) 95: 167. doi:10.1007/s12185-011-0994-5 Abstract
The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph
+) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph + leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit +Sca-1 +Lin − cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph + leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias. Keywords Ph + leukemias Bcr-Abl Fyn References
Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330–40.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–52.
Van Etten RA. Oncogenic signaling: new insights and controversies from chronic myeloid leukemia. J Exp Med. 2007;204:461–5.
Maru Y. Molecular biology of chronic myeloid leukemia. Int J Hematol. 2001;73:308–22.
Chen Y, Peng C, Sullvan C, Li D, Li S. Critical molecular pathway in cancer stem cells of chronic myeloid leukemia. Leukemia. 2010;24:1545–54.
Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood. 2010;115:2872–81.
Hu Y, Liu Y, Pelletier S, Buchdunger E, Warmuth M, Fabbro D, et al. Requirement of Src kinase Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia. Nat Genet. 2004;36:453–61.
Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph + leukemia in mice. Proc Natl Acad Sci USA. 2006;103:16870–5.
Tauchi T, Ohyashiki K. The second generation of BCR-ABL tyrosine kinase inhibitors. Int J Hematol. 2006;83:294–300.
Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM. Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nat Med. 2004;10:1187–9.
Danhauser-Riedl S, Warmuth M, Druker BJ, Emmerich B, Hallek M. Activation of Src kinase p53/56lyn and p59hck by p210bcr/abl in myeloid cells. Cancer Res. 1996;56:3589–96.
Warmuth M, Bergmann M, Priess A, Häuslmann K, Emmerich B, Hallek M. The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr. J Biol Chem. 1997;272:33260–70.
Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690–8.
Zamoyska R, Basson A, Filby A, Legname G, Lovatt M, Seddon B. The influence of the src-family kinases Lck and Fyn on T cell differentiation, survival and activation. Immunol Rev. 2003;191:107–18.
Li S. Src kinase signaling in leukemia. Int J Biochem Cell Biol. 2007;39:1483–8.
Ban K, Gao Y, Amin HM, Howard A, Miller C, Lin Q, et al. BCR-ABL1 mediated up-regulation of Fyn in chronic myelogenous leukemia. Blood. 2008;111:2904–8.
Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci USA. 2006;103:2794–9.
Yagi T, Shigetani Y, Okado N, Tokunaga T, Ikawa Y, Aizawa S. Regional localization of Fyn in adult brain; studies with mice in which
gene was replaced by
. Oncogene. 1993;8:3343–51.
Goto J, Tezuka T, Nakazawa T, Sagara H, Yamamoto T. Loss of Fyn tyrosine kinase on the C57BL/6 genetic background causes hydrocephalus with defects in oligodendrocyte development. Mol Cell Neurosci. 2008;38:203–12.
Morita S, Kojima T, Kitamura T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 2000;7:1063–6.
Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T, et al. Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics. Exp Hematol. 2003;31:1007–14.
Watanabe-Okochi N, Kitaura J, Ono R, Harada H, Harada Y, Komeno Y, et al. AML1 mutations induced MDS and MDS/AML in a mouse BMT model. Blood. 2008;111:4297–308.
Kato N, Kitaura J, Doki N, Komeno Y, Watanabe-Okochi N, Togami K, et al. Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models. Blood. 2011;117:221–33.
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