Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML

Li, Zejuan; Huang, Hao; Li, Yuanyuan; Jiang, Xi; Chen, Ping; Arnovitz, Stephen; Radmacher, Michael D.; Maharry, Kati; Elkahloun, Abdel G.; Yang, Xinan; He, Chunjiang; He, Miao; Zhang, Zhe; Döhner, Konstanze; Neilly, Mary Beth; Price, Colles; Lussier, Yves A.; Zhang, Yanming; Larson, Richard A.; Beau, Michelle M. Le; Caligiuri, Michael A.; Bullinger, Lars; Valk, Peter J.M.; Delwel, Ruud; Löwenberg, Bob; Liu, Paul P.; Marcucci, Guido; Bloomfield, Clara D.; Rowley, Janet D.; Chen, Jianjun

doi:10.1182/blood-2011-10-386235

Cited by 150 publications

(173 citation statements)

References 48 publications

(88 reference statements)

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“…It appears to be the most critical member of PBX family contributing to leukaemogenesis by serving as a cofactor of other homeodomain proteins such as HOX and MEIS 34,35 to control gene expression, and has been identified as a direct target of let-7c, miR-181a/miR-181b, to function in colorectal cancer metastasis and leukaemogenesis, respectively 36,37 . Hence, PBX3 was chosen to validate further whether it was directly targeted by the four miRNAs to regulate a2d1 þ HCC TICs.…”

Section: Resultsmentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel a2d1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that a2d1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of a2d1 þ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

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Section: Resultsmentioning

confidence: 99%

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Han

Zhao

et al. 2015

Nat Commun

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“…It has been demonstrated that expression of miR-181b is associated with lower CR rates and shorter relapse-free survival (RFS) and OS in adult patients with de novo AML (25). Multivariable analysis has revealed that increased expression of miR-181a and miR-181b is also significantly associated with favorable outcomes in cytogenetically abnormal AML with CEBPA mutations and cytogenetically normal AML patients (26)(27)(28)(29). However, an obvious increase of miR-181b-5p was observed in AML serum samples and that higher expression levels of miR-181b-5p in serum are correlated with a poorer OS (30).…”

Section: Discussionmentioning

confidence: 99%

miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1

Zhang

et al. 2014

International Journal of Oncology

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Abstract. Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR-181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment.

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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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Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML

Abstract: Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .

Cited by 150 publications

References 48 publications

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1

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

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