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Chronic Myelomonocytic Leukemia
Pathophysiology
Development of CMML has been associated with chromosomal abnormalities frequently involving the gene encoding PDGFRB—the receptor tyrosine kinase for certain platelet-derived growth factors.1,2 The products of aberrant genes result in constitutive PDGFRB tyrosine kinase activity.2,3 The molecular mechanisms for dysregulated PDGFRB kinase activity in these mutant proteins are not always understood.3
The first fusion gene described in a patient with CMML—ETV6-PDGFRB—arose from the chromosomal translocation t(5;12)(q33;p13) fusing the TEL gene with the gene encoding PDGFRB.4 The ets-related gene TEL, now referred to as ETV6,5 encodes a helix-loop-helix transcription factor that appears to mediate molecular dimerization. Molecular dimerization of the ETV6-PDGFRB fusion protein leads to constitutive phosphorylation of PDGFRB, thereby conferring transforming activity. Preclinical studies have shown that a specific fusion protein that has been associated with CMML—ETV6-PDGFRB—transforms hematopoietic cells and induces a chronic myeloproliferative syndrome in mice.6-8 There are few data on the frequency with which the ETV6-PDGFRB fusion gene occurs in patients with CMML, but the prevalence of this oncogenic mutation appears to be low.1 In a study that screened peripheral blood mononuclear cells from 27 patients with CMML, only 1 of 27 (4%) samples was positive for the ETV6-PDGFRB fusion gene.9
References:
- Cross NC, Reiter A. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia. 2002;16:1207-1212.
- Steer EJ, Cross NC. Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor Beta. Acta Haematol. 2002;107:113-122.
- Jones AV, Cross NC. Oncogenic derivatives of platelet-derived growth factor receptors. Cell Mol Life Sci. 2004;61:2912-2923.
- Golub TR, Barker GF, Lovett M, Gilliland DG, et al. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell. 1994;307-316.
- Andreasson P, Johansson B, Carlsson M, et al. BCR/ABL-negative chronic myeloid leukemia with ETV6/ABL fusion. Genes Chromosomes Cancer. 1997;20:299-304
- Carroll M, Tomasson MH, Barker GF, Golub TR, Gilliland DG. The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci U S A. 1996;93:14845-14850.
- Ritchie KA, Aprikyan AA, Bowen-Pope DF, et al. The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice. Leukemia. 1999;13:1790-1803.
- Tomasson MH, Sternberg DW, Williams IR, et al. Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581. J Clin Invest. 2000;105:423-432.
- Gunby RH, Cazzaniga G, Tassi E, et al. Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia. Haematologica. 2003;88:408-415.
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