The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML

Zangenberg, Mike; Grubach, Lykke; Aggerholm, Anni; Silkjær, Trine; Juhl‐Christensen, Caroline; Nyvold, Charlotte Guldborg; Kjeldsen, Eigil; Ommen, Hans Beier; Hokland, Peter

doi:10.1111/j.1600-0609.2009.01309.x

Cited by 30 publications

(25 citation statements)

References 32 publications

(56 reference statements)

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“…The frequency of HOXA4 and HOXA5 hypermethylation observed in the present study differed from previous studies, possibly resulting from the use of different analytical techniques and threshold levels for 'methylated' sample classification. HOXA4 hypermethylation was previously reported to occur in 64% (by combined bisulfite restriction analysis; COBRA) (4) and 77% (by methylation-sensitive melting curve analysis) (12) of patients compared with 39.4% of patients in the present study. HOXA5 hypermethylation in AML was previously reported as 36% (13) by pyrosequencing and 60 and 59% by COBRA (4,15), compared to 27.6% in the present study.…”

Section: Discussionsupporting

confidence: 41%

“…It has been proposed that HOXA4 downregulation may be associated with promoter methylation status, which was supported by observations in chronic lymphoblastic leukemia (17) and AML (12). HOXA5 promoter methylation regulates gene expression in myeloid leukemia cell lines (15).…”

Section: Discussionmentioning

confidence: 73%

“…AML patients with low expression levels of HOXA4 have a poor prognosis in terms of overall survival (18,19), however, a previous study identified HOXA4 among the genes overexpressed in patients with poor outcome (20). The prognostic role is possibly more complex as it also dependent on the expression of MEIS1 (12).…”

Section: Discussionmentioning

confidence: 99%

“…The HOXA4, HOXA5 and MEIS1 genes are frequently hypermethylated in different types of leukemia, including adult AML (4,12). Previous studies have demonstrated the prognostic value of HOXA4 and HOXA5 methylation in leukemia patients (4,13).…”

Section: Introductionmentioning

confidence: 99%

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Promoter DNA methylation and expression levels of HOXA4, HOXA5 and MEIS1 in acute myeloid leukemia

Musialik

Bujko

Kober

et al. 2015

Molecular Medicine Reports

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Abstract.HOXA genes encode transcription factors, which are crucial for embryogenesis and tissue differentiation and are involved in the early stages of hematopoiesis. Aberrations in HOXA genes and their cofactor MEIS1 are found in human neoplasms, including acute myeloid leukemia (AML). The present study investigated the role of HOXA4, HOXA5 and MEIS1 promoter DNA methylation and mRNA expression in AML. Samples from 78 AML patients and 12 normal bone marrow (BM) samples were included. The levels of promoter DNA methylation were determined using quantitative methylation-specific polymerase chain reaction (PCR; qMSP) and the relative expression levels were measured using reverse transcription quantitative PCR in Ficoll-separated BM mononuclear cells and in fluorescent activated cell sorting-sorted populations of normal hematopoietic progenitors. In total, 38.1 and 28.9% of the patients exhibited high methylation levels of HOXA4 and HOXA5, respectively, compared with the control samples, and MEIS1 methylation was almost absent. An inverse correlation between HOXA4 methylation and expression was identified in a group of patients with a normal karyotype (NK AML). An association between the genes was observed and correlation between the DNA methylation and expression levels of the HOXA gene promoter with the expression of MEIS1 was observed. Patients with favorable chromosomal aberrations revealed a low level of HOXA4 methylation and decreased expression levels of HOXA5 and MEIS1 compared with the NK AML and the adverse cytogenetic risk patients. The NK AML patients with NPM1 mutations exhibited elevated HOXA4 methylation and expression levels of HOXA5 and MEIS1 compared with the NPM1 wild-type patients. Comparison of the undifferentiated BM-derived hematopoietic CD34 + CD38 low , CD34 + CD38 + and CD15 + cells revealed a gradual decrease in the expression levels of these three genes and an increase in HOXA4 promoter methylation. This differentiation-associated variability was not observed in AML, which was classified according to the French-American-British system.

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Section: Discussionsupporting

confidence: 41%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Promoter DNA methylation and expression levels of HOXA4, HOXA5 and MEIS1 in acute myeloid leukemia

Musialik

Bujko

Kober

et al. 2015

Molecular Medicine Reports

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“…Although HOXA overexpression has been linked to adverse prognosis in acute myeloid leukemia, [30][31][32][33] the clini-ETP predicts outcome in HOXA-positive adult T-ALL. …”

Section: Discussionmentioning

confidence: 99%

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

et al. 2016

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G ene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXApositive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursorlike acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected eventfree survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia. Trial Registration: The GRAALL-2003 and studies were registered at

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Aberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients

et al. 2018

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BackgroundImatinib mesylate is a molecularly targeted tyrosine kinase inhibitor drug. It is effectively used in the treatment of chronic myeloid leukemia (CML) patients. However, development of resistance to imatinib mesylate as a result of BCR‐ABL dependent and BCR‐ABL independent mechanisms has emerged as a daunting problem in the management of CML patients. Between these mechanisms, BCR‐ABL independent mechanisms are still not robustly understood.AimTo investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients.Methods and resultsSamples from 175 Philadelphia positive CML patients (83 good response and 92 BCR‐ABL non‐mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut‐off point followed by multiple logistic regression analysis. Log‐Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut‐off point was found to be at 62.5% for both HOXA4 and HOXA5. Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant (P‐value = 0.126 for HOXA4; P‐value = 0.217 for HOXA5).ConclusionHypermethylation of the HOXA4 and HOXA5 promoter is correlated with imatinib resistance and with further investigation, it could be a potential epigenetic biomarker in supplement to the BCR‐ABL gene mutation in predicting imatinib treatment response among CML patients but could not be considered as a prognostic marker.

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The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML

Cited by 30 publications

References 32 publications

Promoter DNA methylation and expression levels of HOXA4, HOXA5 and MEIS1 in acute myeloid leukemia

Promoter DNA methylation and expression levels of HOXA4, HOXA5 and MEIS1 in acute myeloid leukemia

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

Aberrant DNA methylation at HOXA4 and HOXA5 genes are associated with resistance to imatinib mesylate among chronic myeloid leukemia patients

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