scholarly journals The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 345-352 ◽  
Author(s):  
Susan P. Whitman ◽  
Shujun Liu ◽  
Tamara Vukosavljevic ◽  
Laura J. Rush ◽  
Li Yu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Hdac Inhibitors ◽  
Normal Karyotype ◽  
Gain Of Function ◽  
Colony Forming Units ◽  
Selective Sensitivity ◽  
Acute Myeloid

MLL (ALL-1) chimeric fusions and MLL partial tandem duplications (PTD) may have mechanistically distinct contributions to leukemogenesis. Acute myeloid leukemia (AML) blasts with the t(9;11)(p22; q23) express MLL-AF9 and MLL wild-type (WT) transcripts, while normal karyotype AML blasts with the MLLPTD/WT genotype express MLL PTD but not the MLL WT. Silencing of MLL WT in MLLPTD/WT blasts was reversed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and MLL WT induction was associated with selective sensitivity to cell death. Reduction of MLL PTD expression induced MLL WT and reduced blast colony-forming units, supporting opposing functions for MLL PTD and MLL WT whereby the MLL PTD contributes to the leukemic phenotype via a recessive gain-of-function. The coincident suppression of the MLL WT allele with the expression of the MLL PTD allele, along with the functional data presented here, supports the hypothesis that loss of WT MLL function via monoallelic repression contributes to the leukemic phenotype by the remaining mutant allele. These data from primary AML and the pharmacologic reversal of MLL WT silencing associated with a favorable alteration in the threshold for apoptosis suggest that these patients with poor prognosis may benefit from demethylating or histone deacetylase inhibitor therapy, or both.

scholarly journals Efficacy of a New Small-Molecule Inhibitor of Histone Deacetylase 6 (HDAC6) in Preclinical Models of B-Cell Lymphoma and Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5383-5383
Author(s):  
Montserrat Perez-Salvia ◽  
Aldaba Eneko ◽  
Vara Yosu ◽  
Fabre Myriam ◽  
Ferrer Cristina ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
B Cell ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
Histone Deacetylase 6 ◽  
Preclinical Models ◽  
Hdac6 Inhibitor ◽  
Acute Myeloid

Abstract Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitors, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt's cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes. Disclosures Eneko: Quimatryx: Employment. Yosu:Quimatryx: Employment. Myriam:Oncomatryx: Employment. Cristina:Oncomatryx: Employment. González-Barca:Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Fernando:Quimatryx: Consultancy.

Incidence and Prognostic Influence of DNMT3A Mutations in Acute Myeloid Leukemia

2011 ◽  
Vol 29 (21) ◽  
pp. 2889-2896 ◽  
Author(s):  
Felicitas Thol ◽  
Frederik Damm ◽  
Andrea Lüdeking ◽  
Claudia Winschel ◽  
Katharina Wagner ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Direct Sequencing ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Entire Patient Cohort ◽  
Risk Patients ◽  
Acute Myeloid

Purpose To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. Patients and Methods A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). Results DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. Conclusion DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.

Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor–resistant acute myeloid leukemia cells

Blood ◽  
2008 ◽  
Vol 112 (7) ◽  
pp. 2896-2905 ◽  
Author(s):  
Warren Fiskus ◽  
Rekha Rao ◽  
Pravina Fernandez ◽  
Bryan Herger ◽  
Yonghua Yang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Acquired Resistance ◽  
Hdac Inhibitors ◽  
Hsp90 Inhibitor ◽  
Growth Fraction ◽  
Clinical Activity ◽  
Acute Myeloid

Abstract Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI–resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.

scholarly journals The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ali Khateb ◽  
Anagha Deshpande ◽  
Yongmei Feng ◽  
Darren Finlay ◽  
Joo Sang Lee ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Ubiquitin Ligase ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Favorable Prognosis ◽  
Transcriptional Changes ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we find that increased abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patient specimens correlates with poor prognosis. RNF5 inhibition decreases AML cell growth in culture, in patient-derived xenograft (PDX) samples and in vivo, and delays development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition causes transcriptional changes that overlap with those seen upon histone deacetylase (HDAC)1 inhibition. RNF5 induces the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment to and subsequent epigenetic regulation of genes involved in AML maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhances AML cell sensitivity to HDAC inhibitors. Notably, low expression of both RNF5 and HDAC coincides with a favorable prognosis. Our studies identify an ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML, and highlight RNF5/RBBP4 as markers useful to stratify patients for treatment with HDAC inhibitors.

scholarly journals RNF5 Defines Acute Myeloid Leukemia Growth and Susceptibility to Histone Deacetylase Inhibitors

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Ali Khateb ◽  
Anagha Deshpande ◽  
Yongmei Feng ◽  
Ikrame Lazar ◽  
Joo Sang Lee ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Therapeutic Modality ◽  
Advisory Committees ◽  
Acute Myeloid

Acute myeloid leukemia (AML) remains an incurable blood cancer largely due to rapid emergence of resistance to conventional treatments. Thus, new therapeutic modalities are greatly needed to halt AML development. Here, using genetic and xenograft mouse models, we reveal that inhibition of the ubiquitin ligase RNF5 in human AML cell lines and in MLL-AF9-driven AML severely decreased the leukemogenic potential of those cells and prolonged survival of model leukemic mice. These findings suggest the possibility that targeting a single gene, namely RNF5, could effectively inhibit different AML subtypes. We initially focused on RNF5 as its expression is upregulated in AML patient cohorts as well as in AML-derived cell lines compared with normal hematopoietic cells. Furthermore, high RNF5 expression in AML patient specimens correlated with poor prognosis, relapse and short overall patient survival. By contrast, specimens from AML patients who responded to therapy exhibited low RNF5 levels. In vitro, RNF5 loss impaired the clonogenic potential of MLL-AF9-transduced bone marrow cells and markedly attenuated growth and survival of AML but not CML or T-ALL cell lines, in which RNF5 is also highly expressed. High-throughput screen and bioinformatics analysis identified RNF5 and ER-associated degradation (ERAD) components, as augmenting AML cell sensitivity to histone deacetylase (HDAC) inhibition. Indeed, inhibition of RNF5 sensitized AML cells to HDAC inhibitors. Correspondingly, a favorable prognosis was observed in AML patients exhibiting low expression of RNF5 and HDAC. Collectivity, our studies identify a potential new therapeutic modality based on targeting RNF5 to inhibit AML and suggest that RNF5 expression could serve as a prognostic marker and means to stratify patients for treatment with HDAC inhibitors. Disclosures Ofran: AbbVie: Membership on an entity's Board of Directors or advisory committees. Vuori:Bionano Genomics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals RNF5 Regulation of RBBP4 Defines Acute Myeloid Leukemia Growth and Susceptibility to Histone Deacetylase Inhibitors

2020 ◽  
Author(s):  
Ali Khateb ◽  
Anagha Deshpande ◽  
Yongmei Feng ◽  
Joo Sang Lee ◽  
Ikrame Lazar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Ubiquitin Ligase ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Favorable Prognosis ◽  
Transcriptional Changes ◽  
Acute Myeloid

ABSTRACTAcute myeloid leukemia (AML) remains incurable, largely due to its resistance to conventional treatments. Here, we found that increased expression and abundance of the ubiquitin ligase RNF5 contributes to AML development and survival. High RNF5 expression in AML patients correlated with poor prognosis. RNF5 inhibition decreased AML cell growth in culture and in vivo, and blocked development of MLL-AF9–driven leukemogenesis in mice, prolonging their survival. RNF5 inhibition led to transcriptional changes that overlapped with those seen upon HDAC1 inhibition. RNF5 induced the formation of K29 ubiquitin chains on the histone-binding protein RBBP4, promoting its recruitment and subsequent epigenetic regulation of genes involved in AML development and maintenance. Correspondingly, RNF5 or RBBP4 knockdown enhanced the sensitivity of AML cells to histone deacetylase (HDAC) inhibitors. Notably, low expression of RNF5 and HDAC coincided with a favorable prognosis. Our studies identified ERAD-independent role for RNF5, demonstrating that its control of RBBP4 constitutes an epigenetic pathway that drives AML while highlighting RNF5/RBBP4 as markers to stratify patients for treatment with HDAC inhibitors.

scholarly journals A New Strategy to Target Acute Myeloid Leukemia Stem and Progenitor Cells Using Chidamide, a Histone Deacetylase Inhibitor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4925-4925
Author(s):  
Bing Xu ◽  
Yin Li ◽  
Kai Chen ◽  
Yong Zhou ◽  
Yiren Xiao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Hdac Inhibitors ◽  
Mechanistic Study ◽  
G1 Arrest ◽  
Dependent Manner ◽  
Mitochondria Membrane Potential ◽  
Acute Myeloid

Abstract Leukemia stem cells (LSCs) are responsible for treatment failure and relapse in acute myeloid leukemia (AML). Therefore, development of novel LSCs-targeting therapeutic strategies is of crucial clinical importance to improve the treatment outcomes of AML. Histone deacetylase (HDAC) inhibitors have emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer. HDAC inhibitors have shown potent and specific anticancer stem cell activities in preclinical studies. Chidamide, a novel benzamide-type selectively HDAC inhibitor, has been reported to induce G1 arrest and apoptosis in the relatively mature progenitor population, whereas its effect on primitive LSCs has not been clarified. In this study, we demonstrated that chidamide specifically induces apoptosis in LSC-like cells and primary AML CD34+ cells in a concentration- and time-dependent manner. Our further molecular mechanistic study uncovered that chidamide induces LSCs death by activation of reactive oxygen species (ROS). It compromises the mitochondria membrane potential, modulates anti-apoptotic and pro-apoptotic proteins in BCL2 family and activates caspase-3 leading to PARP degradation. Meanwhile, chidamide activates CD40 and modulates its downstream signaling pathways, JNK and NFκB. The results of this study suggest that chidamide may be a novel LSC-targeting agent for AML therapeutics. Disclosures No relevant conflicts of interest to declare.

Down-Regulation of Microrna 223 and 148a Mediates Resistance of Human Acute Myeloid Leukemia Cells to Pan-Histone Deacetylase (HDAC) Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2401-2401
Author(s):  
Jianguang Chen ◽  
Veena Kandaswamy ◽  
Warren Fiskus ◽  
Yongchao Wang ◽  
Rekha Rao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Myeloid Leukemia ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
K562 Cells ◽  
Methyl Transferase ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Abstract 2401 Poster Board II-378 MicroRNA (miR) alterations are highly involved in the pathogenesis of leukemia. However, the role of miRs in de novo or acquired resistance of cancer cells to therapeutic agents has not been fully elucidated. Recently, we reported the isolation and characterization of HL-60/LR cells, derived from human acute myeloid leukemia HL-60 cells, that are resistant to pan-histone deacetylase (HDAC) inhibitors (HDIs), including vorinostat and panobinostat (Blood. 2008; 112: 2896). To explore the role of miRs in acquiring resistance to HDIs, we performed a miR microarray analysis of the parental HL-60 and HL-60/LR cells. Compared to HL-60 cells, expression of thirteen microRNAs were discovered to be significantly increased (> 4-fold) and fourteen miRs were markedly down-regulated (> 4-fold) in HL-60/LR cells. Alterations in the expression of three of the most promising upregulated (miR-21, miR-126 and miR-146a) and down-regulated (miR-223, miR-148a and miR-342) miRs were confirmed by Q-PCR in HL-60/LR cells. The expression of miR-223, miR-148a and miR-342 was also significant lower in the relatively HDI-resistant K562 cells as compared to HDI-sensitive U937 and HL-60 cells. Conversely, miR-126 and miR-146a expressions were higher in K562 cells compared to U937 and HL-60 cells. Short term (24 hours) treatment with panobinostat (10 to 50 nM) did not alter the expression of miR-223 or miR-148a expression in HL-60 cells. As compared to treatment with either agent alone, co-treatment with the histone methyl transferase EZH2 antagonist 3-deazaneplanocin (DZnep, 1.0 uM) and DNA methyl transferase inhibitor decitabine (2.0 uM) induced miR-223 and miR-148a levels and mediated apoptosis of HL-60/LR cells, suggesting that an epigenetic silencing mechanism(s) may be involved in the down-modulation of miR-223 and miR-148a in HL-60/LR cells. To determine whether the alterations in the miR levels were mechanistically involved in conferring resistance to HDIs, we engineered through retroviral transduction stable ectopic expressions of miR-223, miR-148a and miR-342 into HL-60/LR cells and miR-21 and miR-146a into HL-60 cells. Ectopic expression of miR-223 and miR-148a significantly increased the sensitivity of HL-60/LR cells to panobinostat and vorinostat. In contrast, re-expression of miR-342 had an insignificant effect on HDI sensitivity. Increased expression of miR-21 and miR-146a did not confer resistance to the HDIs in HL-60 and U937 cells. Next, by Western analyses, we compared the expression levels of several of the predicted target proteins of miR-223 and miR-148a, (as predicted by the computer programs TargetScan and picTAR), in HL-60 versus HL-60/LR cells, as well as in the HL-60/LR cells with stable ectopic expression of miR-223 and miR-148a. Several candidate proteins including GRP94, Ribosomal protein S6 kinase MSK1, MEF2C and DNMT1 showed higher level of expression in HL-60/LR versus HL-60 and were down-regulated in miR-223 or miR-148a transduced HL-60/LR cells, suggesting that these proteins may confer resistance against HDI. Parenthetically, miR-223 was shown to be a myeloid-specific miR which negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 mutant mice have an expanded granulocytic compartment resulting from an increase in the number of granulocyte progenitors. In summary, our observations indicate that high miR-223 and miR-148a levels may be predictive biomarkers for sensitivity to HDIs in human AML cells. Additionally, induction of miR-223 and miR-148a by EZH2 antagonist may increase sensitivity and overcome resistance to HDIs in human AML cells. Targeting the levels and/or activity of the miR-223 and miR-148a target proteins may also be an effective strategy in enhancing the activity of HDI based combination therapy against AML. Disclosures: Atajada: Novartis: Employment. Bhalla:Merck: Honoraria; Novartis: Honoraria, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document