Balanced translocations

As already discussed, the presence of balanced translocations is much more typical of AML than of MDS. Nevertheless they do occur occasionally in MDS and have led to the identification of several novel genes.

The t(5;12) is found in patients with CMML. The translocation creates a fusion gene containing the 5' portion of the TEL gene and the 3' portion of the platelet-derived growth factor gene (PDGFRfi), a tyrosine kinase gene. Treatment of such cases with inatimib mesylate has given durable responses.

A small number of cases of MDS with balanced translocations involving chromosomal band 11p15 and another chromosome, for example t(11;17)(p15;q21) and t(11;12)(p15;q13), have been described, mostly arising after cytotoxic therapy. In all cases analyzed to date, the NUP98 gene at 11p15 is fused to another gene on the partner chromosome, resulting in a novel fusion protein. The t(11;16)(p23;p13.3) has been reported in patients with t-MDS. The MLL gene on chromosome 11 is fused to the CBP gene on chromosome 16; MLL is a multifunction protein that regulates Hox gene expression during development.

A number of rearrangements involving chromosome band 3q26 have been reported in de novo MDS and t-MDS. The two related genes MDS1/EVI1 and EVI1 map to 3q26 and encode nuclear transcription factors containing DNA-binding zinc finger domains. They have opposite functions as transcription factors. EVI1 is frequently activated inappropriately by chromosomal rearrangements at 3q26, leading to the development of myeloid leukemia.

The t(3;3)(q21;26) has been reported in de novo MDS and t-MDS. The t(3;21)(q26;q22) has been described in t-MDS/t-AML. In this translocation the AML1 gene at 21q22 is fused to either EVI1 or MDS1 at 3q26 or to both (AML1-MDS1-EVI1 complex fusion) or EAP. EVI1, in particular, is activated as a result of the translocation. AML1 fuses with MDS1-EVI1 in frame, resulting in the loss of the first 12 amino acids and producing a novel EVI1 protein. The novel EVI1 protein causes arrested differentiation, which leads to apoptosis in vitro. It has been shown recently that MDS-EVI1 enhances transforming growth factor-pi (TGF-P1) signaling and strengthens its growth-inhibitory effect, but the leukemia-associated fusion protein AML1-MDS1-EVI1 product of the t(3;21) abrogates growth inhibition in response to TGF-pi. Forced expression of EVI1 in embryonic stem cells has been demonstrated to increase cell growth—of megakaryocytic colonies in particular.

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