Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Voso, Maria Teresa; Scardocci, Alessandra; Guidi, Francesco; Zini, Gina; Mario, Antonella Di; Pagano, Livio; Hohaus, Stefan; Leone, Giuseppe

doi:10.1182/blood-2003-07-2249

Cited by 77 publications

(62 citation statements)

References 18 publications

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“…Accordingly, hypermethylation of several genes has been reported in t-AML (Christiansen et al, 2003;Voso et al, 2004;Larson and Le Beau, 2005), and ionising radiation has been shown to induce hypermethylation.…”

Section: Discussionmentioning

confidence: 99%

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

et al. 2006

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BRCA1 plays a pivotal role in the repair of DNA damage, especially following chemotherapy and ionising radiation. We were interested in the regulation of BRCA1 expression in acute myeloid leukaemia (AML), in particular in therapy-related forms (t-AML). Using real-time PCR and Western blot, we found that BRCA1 mRNA was expressed at barely detectable levels by normal peripheral blood granulocytes, monocytes and lymphocytes, whereas control BM-mononuclear cells and selected CD34 þ progenitor cells displayed significantly higher BRCA1 expression (P ¼ 0.0003). Acute myeloid leukaemia samples showed heterogeneous BRCA1 mRNA levels, which were lower than those of normal bone marrows (P ¼ 0.0001). We found a high frequency of hypermethylation of the BRCA1 promoter region in AML (51/133 samples, 38%), in particular in patients with karyotypic aberrations (P ¼ 0.026), and in t-AML, as compared to de novo AML (76 vs 31%, P ¼ 0.0002). Examining eight primary tumour samples from hypermethylated t-AML patients, BRCA1 was hypermethylated in three of four breast cancer samples, whereas it was unmethylated in the other four tumours. BRCA1 hypermethylation correlated to reduced BRCA1 mRNA (P ¼ 0.0004), and to increased DNA methyltransferase DNMT3A (P ¼ 0.003) expression. Our data show that reduced BRCA1 expression owing to promoter hypermethylation is frequent in t-AML and that this could contribute to secondary leukaemogenesis.

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Section: Discussionmentioning

confidence: 99%

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

et al. 2006

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“…[88][89][90][91] Secondary leukemia is often inhibited apoptotic response. 92 Chemotherapy-related leukemias account for 10-20% of all acute myeloid leukemia (AML) cases and are resistant. 88 Secondary tumors include brain tumors, leukemia, breast cancer, thyroid cancer, bone and soft-tissue sarcoma.…”

Section: Secondary Cancersmentioning

confidence: 99%

“…93 Radiation, alkylating agents and topoisomerase II inhibitors are most common causes for secondary tumors. [89][90][91][92][93][94] …”

Section: Secondary Cancersmentioning

confidence: 99%

Carcinogenesis, cancer therapy and chemoprevention

Blagosklonny

2005

Cell Death Differ

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Carcinogenesis and cancer therapy are two sides of the same coin, such that the same cytotoxic agent can cause cancer and be used to treat cancer. This review links carcinogenesis, chemoprevention and cancer therapy in one process driven by cytotoxic agents (carcinoagents) that select either for or against cells with oncogenic alterations. By unifying therapy and cancer promotion and by distinguishing nononcogenic and oncogenic mechanisms of resistance, I discuss anticancer-and chemopreventive agent-induced carcinogenesis and tumor progression and, vice versa, carcinogens as anticancer drugs, anticancer drugs as chemopreventive agents and exploiting oncogene-addiction and drug resistance for chemoprevention and cancer therapy.

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“…Up to now, four other members of the DAPK family have been identified. DAPK1, the closest homolog of DAPK2, is suggested to act as a tumor suppressor (Bialik and Kimchi, 2006) and is epigenetically silenced in a variety of human cancers (Katzenellenbogen et al, 1999;Esteller et al, 2001;Maruyama et al, 2001;Voso et al, 2004;Christoph et al, 2006). Similar to DAPK1, DAPK2 has been shown to participate in tumornecrosis factor-a and FAS-receptor-induced cell death (Inbal et al, 2000;Shohat et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

et al. 2008

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Death-associated protein kinase 2 (DAPK2) belongs to a family of proapoptotic Ca 2 þ /calmodulin-regulated serine/ threonine kinases. We recently identified DAPK2 as an enhancing factor during granulocytic differentiation. To identify transcriptional DAPK2 regulators, we cloned 2.7 kb of the 5 0 -flanking region of the DAPK2 gene. We found that E2F1 and Kru¨ppel-like factor 6 (KLF6) strongly activate the DAPK2 promoter. We mapped the E2F1 and KLF6 responsive elements to a GC-rich region 5 0 of exon 1 containing several binding sites for KLF6 and Sp1 but not for E2F. Moreover, we showed that transcriptional activation of DAPK2 by E2F1 and KLF6 is dependent on Sp1 using Sp1/KLF6-deficient insect cells, mithramycin A treatment to block Sp1-binding or Sp1 knockdown cells. Chromatin immunoprecipitation revealed recruitment of Sp1 and to lesser extent that of E2F1 and KLF6 to the DAPK2 promoter. Activation of E2F1 in osteosarcoma cells led to an increase of endogenous DAPK2 paralleled by cell death. Inhibition of DAPK2 expression resulted in significantly reduced cell death upon E2F1 activation. Similarly, KLF6 expression in H1299 cells increased DAPK2 levels accompanied by cell death that is markedly decreased upon DAPK2 knockdown. Moreover, E2F1 and KLF6 show cooperation in activating the DAPK2 promoter. In summary, our findings establish DAPK2 as a novel Sp1-dependent target gene for E2F1 and KLF6 in cell death response.

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Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes

Cited by 77 publications

References 18 publications

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

Reduced BRCA1 expression due to promoter hypermethylation in therapy-related acute myeloid leukaemia

Carcinogenesis, cancer therapy and chemoprevention

DAPK2 is a novel E2F1/KLF6 target gene involved in their proapoptotic function

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