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Development of Megakaryoblastic Leukaemia in Runx1-Evi1 Knock-In Chimaeric Mouse

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Development of Megakaryoblastic Leukaemia in Runx1-Evi1 Knock-In Chimaeric Mouse Letter to the Editor 1458 control. The Mcl-1-specific T-cell clone did not kill this cell line Ms. Bodil K. Jakobsen, Department of Clinical Immunology, (Figure 1c). University Hospital, Copenhagen, for HLA-typing of patient blood The lower rates of relapse in allogeneic transplantation samples. This study was supported by grants from the Danish compared with autologous bone marrow transplantation, the Medical Research Council, The Novo Nordisk Foundation, The striking clinical benefit of donor-lymphocyte infusions as well as Danish Cancer Society, The John and Birthe Meyer Foundation, the finding that human T cells can destroy chemotherapy- and Danish Cancer Research Foundation. resistant cell lines from chronic myeloid leukemia and multiple RB Sørensen1, OJ Nielsen2, P thor Straten1 and MH Andersen1 myeloma, have prompted development of immunotherapeutic 1 strategies against hematological cancers.3 Among these ap- Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark and proaches, active specific immunization or vaccination is 2Department of Hematology, State University Hospital, emerging as a valuable tool to boost the adaptive immune Copenhagen, Denmark. system against malignant cells. In this regard, the identification E-mail: [email protected] of leukemia-associated antigens is crucial. However, very few antigens are characterized in a conceptual framework in which the biology, microenvironment, and conventional disease management have been taken into consideration. Myeloid cell References factor-1 (Mcl-1) is a death-inhibiting member of the Bcl-2 family that is expressed in early monocyte differentiation. Elevated 1 Andersen MH, Becker JC, thor Straten P. The anti-apoptotic member levels of Mcl-1 have been reported for a number of solid and of the Bcl-2 family Mcl-1 is a CTL target in cancer patients. hematopoitic cancers, for example, B-cell chronic lymphocytic Leukemia 2005; 19: 484–485. 4–6 leukemia (B-CLL) and in AML and ALL upon relapse. In B-CLL 2 Andersen MH, Kvistborg P, Becker JC, thor Straten P. Identification patients, higher levels of Mcl-1 are strongly correlated with of an HLA-A1 restricted CTL epitope from Mcl-1. Leukemia 2005; failure to achieve complete remission after single-agent therapy. 19: 1084–1085. In multiple myeloma, Mcl-1 plays an important role in the 3 Mocellin S, Semenzato G, Mandruzzato S, Riccardo RC. Part II: 7 Vaccines for haematological malignant disorders. Lancet Oncol survival of malignant cells. We have reported that spontanous 2004; 5: 727–737. Mcl-1-specific T-cell responses are frequent in cancer patients 4 Zapata JM, Krajewska M, Krajewski S, Huang RP, Takayama S, and that these T-cells are highly cytotoxic against cancer cells. Wang HG et al. Expression of multiple apoptosis-regulatory genes in Hence, Mcl-1 appears to be a very attactrive target for human breast cancer cell lines and primary tumors. Breast Cancer anticancer immunotherapy both in hematopoetic and solid Res Treat 1998; 47: 129–140. cancers. 5 Tang L, Tron VA, Reed JC, Mah KJ, Krajewska M, Li G et al. Expression of apoptosis regulators in cutaneous malignant melano- ma. Clin Cancer Res 1998; 4: 1865–1871. 6 Shangary S, Johnson DE. Recent advances in the development of Acknowledgements anticancer agents targeting cell death inhibitors in the Bcl-2 protein family. Leukemia 2003; 17: 1470–1481. We thank Inge Marie Svane, Herlev University Hospital for 7 Zhang B, Gojo I, Fenton RG. Myeloid cell factor-1 is a critical collection of blood samples. We thank Professor A. Svejgaard and survival factor for multiple myeloma. Blood 2002; 99: 1885–1893. Development of megakaryoblastic leukaemia in Runx1-Evi1 knock-in chimaeric mouse Leukemia (2006) 20, 1458–1460. doi:10.1038/sj.leu.2404281; progenitors. Here, we report the development of megakaryo- published online 8 June 2006 blastic leukaemia in Runx1-Evi1 knock-in chimaeric mouse. Runx1-Evi1 knock-in chimaeric mice were created by injecting recombinant TT2 ES cells3 into wild-type blastocyst.4 Chromosomal translocations involving the Runx1 gene create We created six of such chimaeric mice, and five of them showed various chimaeric proteins that are believed to cause human sudden deaths after 7 months of age without any significant leukaemia. Runx1-ETO and Runx1-Evi1, generated as conse- finding in post mortem. Interestingly, one of the chimaeric mice quences of t(8;21) and t(3;21), respectively, share molecular that died at 5 months of age showed marked hepatospleno- structural similarities; they both contain DNA-binding domain megaly. Wright–Giemsa staining of stump preparation from the of Runx1 and transcriptional repression domains from either enlarged spleen demonstrated massive infiltration of large ETO or Evi1. Despite such similarity, the subtypes of leukaemia dysplastic cells, some of which contained multi-lobulated related to each of the chimaeric protein are different; Runx1- nuclei with various size of cytoplasm reminiscent of megakaryo- ETO typically occurs with acute myelocytic leukaemia of M2 blastic leukaemia (Figure 1a). Histology section showed subtype in the French–American–British classification, whereas disrupted gross architecture of the spleen, with white and red Runx1-Evi1 is mostly associated with megakaryoblastic leukae- pulp intermingling (Figure 1c). In the liver, substantial infiltra- mia of M7 subtype or megakaryoblastic crisis in chronic tion of leucocytes was observed around the portal vein myelocytic leukaemia. Experimental animals that express the (Figure 1d). Most of the infiltrating cells consisted of reactive fusion proteins in the hematopoietic cells have been created to neutrophils, with partial presence of the dysplastic megakaryo- recapitulate the diseases. Both Runx1-ETO transgenic1 and cytic cells observed in the spleen. Multiple fibrin thrombi were conditional knock-in2 mice do not develop leukaemia by itself identified in the portal vein, indicating the occurrence of and require additional genetic aberrations to transform myeloid disseminated intravascular coagulation. These findings all Leukemia Letter to the Editor 1459 Figure 1 Development of megakaryoblastic leukaemia in Runx1-Evi1 chimaeric mouse. (a) Wright–Giemsa staining of stump preparation from spleen (objective lens (OL), Â 40/0.65; original magnification (OM), Â 400). (b) Electron micrograph of spleen cells (OM, Â 3000). M, myeloid cell; Meg, megakaryocytic cell. (c, d) Hematoxylin–eosin staining of sections from spleen (c) (OL, Â 10/0.40; OM, Â 100) and liver (d) (OL, Â 20/ 0.70; OM, Â 200). indicate an aggressive form of leukaemia. The electron Health, Labour and Welfare, and Japanese Society for the microscopic analysis of the infiltrating cells in the spleen Promotion of Science. showed 20% of the cells positive for platelet-peroxidase, K Maki1, T Yamagata1, I Yamazaki2, H Oda3 and K Mitani1 substantiating megakaryocytic origin of the leukaemic cells 1 (Figure 1b). Taken together, we conclude that this chimaeric Department of Haematology, Dokkyo Medical University School of Medicine, Tochigi, Japan; mouse developed megakaryoblastic leukaemia. 2Department of Clinical Laboratory and Pathology, The key aspect of our observation is that Runx1-Evi1 protein is Inoue Memorial Hospital, Chiba, Japan and leukaemogenic per se, unlike Runx1-ETO. Such clear difference 3Department of Pathology, Tokyo Women’s Medical in the pathophysiological outcome likely arises from the Evi1 University, Tokyo, Japan portion of Runx1-Evi1 protein. Evi1 is reported to stimulate E-mail: [email protected] activator protein 1 activity,5 repress transforming growth factor- b signaling,6 and inhibit c-Jun N-terminal kinase function.7 Such versatile function of Evi1 may underlie stronger oncogenic capacity of Runx1-Evi1 than Runx1-ETO. Another important References aspect is that the affected lineage in human is conserved in the experimental animal. Our observation indicates strong causal 1 Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hether- relationship between the expression of Runx1-Evi1 protein and ington CJ et al. AML1-ETO expression is directly involved in the megakaryoblastic leukaemia. Indeed, the Runx1-Evi1 chimaeric development of acute myeloid leukemia in the presence of gene was isolated from a patient developing megakaryoblastic additional mutations. Proc Natl Acad Sci USA 2001; 98: 10398– 10403. crisis in chronic myelocytic leukaemia that accompanied 2 Higuchi M, O’Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing 8 emergence of t(3;21). It is unknown whether Runx1-Evi1 is JR. Expression of a conditional AML1-ETO oncogene bypasses preferentially oncogenic in megakaryoblast, or show exclusive embryonic lethality and establishes a murine model of human maturation block in the megakaryocytic lineage when expressed t(8;21) acute myeloid leukemia. Cancer Cell 2002; 1: 63–74. in early haematopoietic cells. Foetal liver cells from Runx1-Evi1 3 Yagi T, Tokunaga T, Furuta Y, Nada S, Yoshida M, Tsukada T et al. A knock-in heterozygous embryo can give rise to dysplastic novel ES cell line, TT2, with high germline-differentiating potency. 4 Anal Biochem 1993; 214: 70–76. megakaryocytes. Such abnormal progenitors may have per- 4 Maki K, Yamagata T, Asai T, Yamazaki I, Oda H, Hirai H et al. Dys- sisted in the adult bone marrow and expanded to cause massive plastic definitive hematopoiesis in AML1/EVI1 knock-in embryos. infiltration of the megakaryoblasts in the liver and spleen. Blood 2005; 106: 2147–2155. 5 Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y, Hirai H. Evi-1 raises AP-1 activity and stimulates c-fos promoter transactivation with dependence on the second zinc finger domain. J Biol Chem Acknowledgements 1994; 269: 24020–24026. 6 Kurokawa M, Mitani K, Irie K, Matsuyama T, Takahashi T, Chiba S This work was supported by Grants-in-Aid from the Ministries in et al. The oncoprotein Evi-1 represses TGF-b signalling by inhibiting Japan of Education, Culture, Sports, Science and Technology, and Smad3. Nature 1998; 394: 92–96. Leukemia Letter to the Editor 1460 7 Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, 8 Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H Ogawa S et al.
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