A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on October 15, 2009 under Uncategorized | 
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Authors: M Veeraputhiran
& K Mangan (Source: Bone Marrow Transplantation)
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Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies.
Cancer Res. 2009 Oct 13;
Authors: Ye Y, McDevitt MA, Guo M, Zhang W, Galm O, Gore SD, Karp JE, Maciejewski JP, Kowalski J, Tsai HL, Gondek LP, Tsai HC, Wang X, Hooker C, Smith BD, Carraway HE, Herman JG
Complete loss or deletion of the long arm of chromosome 5 is frequent in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). The putative gene(s) deleted and responsible for the pathogenesis of these poor prognosis hematologic disorders remain controversial. This study is a comprehensive analysis of previously implicated and novel genes for epigenetic inactivation in AML and MDS. In 146 AML cases, methylation of CTNNA1 was frequent, and more common in AML patients with 5q deletion (31%) than those without 5q deletion (14%), whereas no methylation of other 5q genes was observed. In 31 MDS cases, CTNNA1 methylation was only found in high-risk MDS (>/=RAEB2), but not in low-risk MDS (<RAEB2), indicating that CTNNA1 methylation might be important in the transformation of MDS to AML. CTNNA1 expression was lowest in AML/MDS patients with CTNNA1 methylation, although reduced expression was found in some patients without promoter methylation. Repressive chromatin marks (H3K27me3) at the promoter were identified in CTNNA1-repressed AML cell lines and primary leukemias, with the most repressive state correlating with DNA methylation. These results suggest progressive, acquired epigenetic inactivation at CTNNA1, including histone modifications and promoter CpG methylation, as a component of leukemia progression in patients with both 5q- and non-5q- myeloid malignancies. [Cancer Res 2009;69(21):OF1-9].
PMID: 19826047 [PubMed - as supplied by publisher]
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The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.
Cancer Cell. 2009 Sep 8;16(3):232-45
Authors: Klemm L, Duy C, Iacobucci I, Kuchen S, von Levetzow G, Feldhahn N, Henke N, Li Z, Hoffmann TK, Kim YM, Hofmann WK, Jumaa H, Groffen J, Heisterkamp N, Martinelli G, Lieber MR, Casellas R, Müschen M
Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.
PMID: 19732723 [PubMed - indexed for MEDLINE]
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Imatinib resistance and progression of CML to blast crisis: somatic hypermutation AIDing the way.
Cancer Cell. 2009 Sep 8;16(3):174-6
Authors: Strout MP, Schatz DG
Very little is known about how acquired oncogenic mutations arise. In this issue of Cancer Cell, Klemm and colleagues present evidence supporting a role for the antibody diversification enzyme activation-induced deaminase (AID) in the generation of mutations associated with disease progression and drug resistance in chronic myeloid leukemia.
PMID: 19732715 [PubMed - indexed for MEDLINE]
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Targeted cancer therapy: promise and reality.
Adv Cancer Res. 2007;97:295-319
Authors: Klein S, Levitzki A
Signal transduction therapy for cancer targets specific molecular elements that are essential for survival of the tumor. Gleevec has a profound effect on early phase chronic myeloid leukemia because it inhibits the major driving factor of the tumor, BCR-ABL. Almost all other cancers depend on several factors, and blocking a single signal transduction factor is largely ineffective. Effective signal transduction therapy will entail finding the appropriate combination of signal transduction inhibitors for each cancer. We discuss the use of preclinical animal models to predict successful signal transduction therapy in the clinic, and conclude that their utility is limited.
PMID: 17419951 [PubMed - indexed for MEDLINE]
