Gene Summary

Gene:KMT2A; lysine methyltransferase 2A
Summary:This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase 2A
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (17)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Acute Lymphocytic Leukaemia (ALL)t(10;11)(p12;q23) AF10-MLL translocation in Acute Leukaemia View Publications122
Acute Lymphocytic Leukaemia (ALL)t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia View Publications18
Acute Lymphocytic Leukemia (ALL), childins(5;11)(q31;q31q23) MLL-AFF4 in Infant Acute lymphoblastic Leukemia View Publications12
Acute Myeloid Leukaemia (AML)t(1;11)(p32;q23) MLL-EPS15 fusion in Acute Myelogeneous Leukemia View Publications11
Acute Lymphocytic Leukaemia (ALL)t(10;11) MLL-TET1 rearrangement in acute leukemias View Publications4
Haematological MalignanciesKMT2A and Haematological Malignancies View Publications2
Leukaemiat(10;11)(p11.2;q23) ABI1-MLL translocation in Leukemia View Publications2
-KMT2A and Residual Disease View Publications2
Lung CancerKMT2A and Lung Cancer View Publications1
Prostate CancerKMT2A and Prostate Cancer View Publications1
Acute Myeloid Leukaemia (AML)t(1;11) (q21;q23) in Leukemia
The MLL gene on chromosome 11 is frequently involved in translocations with a range of other genes. Tse et al, 1995 identified the AF1q (MLLT11) gene and t(1;11)(q21;q23) translocation of AF1q/MLL. In a series of 45 leukemia patients with MLL rearagements Cerveira et al, 2012 found 2 (4%) had the AF1q/MLL translocation.
Acute Lymphocytic Leukemia (ALL), childt(4;11)(q21;q23) in Infant Leukaemia
Acute Myeloid Leukaemia (AML)t(6;11)(q27;q23) in Acute Myeloid Leukemia
Acute Lymphocytic Leukaemia (ALL)t(4;11)(q21;q23) MLL-AFF1 in adult acute lymphoblastic leukemia
Acute Myeloid Leukaemia (AML)t(9;11) in Acute Myeloid Leukaemia
-t(11;17) ALL1-MLLT6 in Acute Leukaemias
Leukaemiat(11;19)(q23;p13) in Leukaemia

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KMT2A (cancer-related)

Mousavian Z, Nowzari-Dalini A, Stam RW, et al.
Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia.
Cell Oncol (Dordr). 2017; 40(1):33-45 [PubMed] Related Publications
PURPOSE: Despite vast improvements that have been made in the treatment of children with acute lymphoblastic leukemia (ALL), the majority of infant ALL patients (~80 %, < 1 year of age) that carry a chromosomal translocation involving the mixed lineage leukemia (MLL) gene shows a poor response to chemotherapeutic drugs, especially glucocorticoids (GCs), which are essential components of all current treatment regimens. Although addressed in several studies, the mechanism(s) underlying this phenomenon have remained largely unknown. A major drawback of most previous studies is their primary focus on individual genes, thereby neglecting the putative significance of inter-gene correlations. Here, we aimed at studying GC resistance in MLL-rearranged infant ALL patients by inferring an associated module of genes using co-expression network analysis. The implications of newly identified candidate genes with associations to other well-known relevant genes from the same module, or with associations to known transcription factor or microRNA interactions, were substantiated using literature data.
METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with GC resistance in MLL-rearranged infant ALL patients. Significant gene ontology (GO) terms and signaling pathways enriched in relevant modules were used to provide guidance towards which module(s) consisted of promising candidates suitable for further analysis.
RESULTS: Through gene co-expression network analysis a novel set of genes (module) related to GC-resistance was identified. The presence in this module of the S100 and ANXA genes, both well-known biomarkers for GC resistance in MLL-rearranged infant ALL, supports its validity. Subsequent gene set net correlation analyses of the novel module provided further support for its validity by showing that the S100 and ANXA genes act as 'hub' genes with potentially major regulatory roles in GC sensitivity, but having lost this role in the GC resistant phenotype. The detected module implicates new genes as being candidates for further analysis through associations with known GC resistance-related genes.
CONCLUSIONS: From our data we conclude that available systems biology approaches can be employed to detect new candidate genes that may provide further insights into drug resistance of MLL-rearranged infant ALL cases. Such approaches complement conventional gene-wise approaches by taking putative functional interactions between genes into account.

Wu J, Xiao L, Zhou H, et al.
ZFX modulates the growth of human leukemic cells via B4GALT1.
Acta Biochim Biophys Sin (Shanghai). 2016; 48(12):1120-1127 [PubMed] Related Publications
Zinc finger protein X-linked (ZFX) is a key regulator of both embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs), which is required for both Notch intracellular domain (NotchIC)-induced acute T-cell leukemia and MLL-AF9-induced myeloid leukemia in mouse models. However, the role of ZFX and its underlying mechanism in human leukemic cells remain unclear yet, though accumulating data have demonstrated that ZFX is aberrantly expressed in various human tumors and plays an important role. Herein, we found that ZFX was aberrantly expressed in various human leukemic cell lines and primary cells from leukemia patients compared with control cells. The silence of ZFX led to the growth suppression through either the deregulated cell cycle or the induction of apoptosis in various cells including K562, Jurkat, Namalwa, and THP-1 cells. The gene expression analysis revealed that UDP-Gal:βGlcNAc β 1,4-galactosyltransferase, polypeptide 1 (B4GALT1) was significantly down-regulated upon ZFX silencing, which is implicated in the response of K562 cells to the treatment of imatinib mesylate (IM). In addition, lectin blot assay showed that the galactosylation of glycoproteins in K562 cells was suppressed upon ZFX silencing. Interestingly, overexpression of B4GALT1 restored the growth and conferred drug resistance to ZFX-silenced cells. Taken together, we have demonstrated that ZFX is aberrantly expressed in multiple human leukemic cells and it modulates the growth and drug response of leukemic cells partially via B4GALT1, which suggests that ZFX is a new regulator of leukemic cells and warrants intensive investigations on this 'stemness' regulator in these deadly diseases.

Akhter A, Mughal MK, Elyamany G, et al.
Multiplexed automated digital quantification of fusion transcripts: comparative study with fluorescent in-situ hybridization (FISH) technique in acute leukemia patients.
Diagn Pathol. 2016; 11(1):89 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The World Health Organization (WHO) classification system defines recurrent chromosomal translocations as the sole diagnostic and prognostic criteria for acute leukemia (AL). These fusion transcripts are pivotal in the pathogenesis of AL. Clinical laboratories universally employ conventional karyotype/FISH to detect these chromosomal translocations, which is complex, labour intensive and lacks multiplexing capacity. Hence, it is imperative to explore and evaluate some newer automated, cost-efficient multiplexed technologies to accommodate the expanding genetic landscape in AL.
METHODS: "nCounter® Leukemia fusion gene expression assay" by NanoString was employed to detect various fusion transcripts in a large set samples (n = 94) utilizing RNA from formalin fixed paraffin embedded (FFPE) diagnostic bone marrow biopsy specimens. This series included AL patients with various recurrent translocations (n = 49), normal karyotype (n = 19), or complex karyotype (n = 21), as well as normal bone marrow samples (n = 5). Fusion gene expression data were compared with results obtained by conventional karyotype and FISH technology to determine sensitivity/specificity, as well as positive /negative predictive values.
RESULTS: Junction probes for PML/RARA; RUNX1-RUNX1T1; BCR/ABL1 showed 100 % sensitivity/specificity. A high degree of correlation was noted for MLL/AF4 (85 sensitivity/100 specificity) and TCF3-PBX1 (75 % sensitivity/100 % specificity) probes. CBFB-MYH11 fusion probes showed moderate sensitivity (57 %) but high specificity (100 %). ETV6/RUNX1 displayed discordance between fusion transcript assay and FISH results as well as rare non-specific binding in AL samples with normal or complex cytogenetics.
CONCLUSIONS: Our study presents preliminary data with high correlation between fusion transcript detection by a throughput automated multiplexed platform, compared to conventional karyotype/FISH technique for detection of chromosomal translocations in AL patients. Our preliminary observations, mandates further vast validation studies to explore automated molecular platforms in diagnostic pathology.

Xia J, Hu Z, Yoshihara S, et al.
Modeling Human Leukemia Immunotherapy in Humanized Mice.
EBioMedicine. 2016; 10:101-8 [PubMed] Free Access to Full Article Related Publications
The currently available human tumor xenograft models permit modeling of human cancers in vivo, but in immunocompromised hosts. Here we report a humanized mouse (hu-mouse) model made by transplantation of human fetal thymic tissue plus hematopoietic stem cells transduced with a leukemia-associated fusion gene MLL-AF9. In addition to normal human lymphohematopoietic reconstitution as seen in non-leukemic hu-mice, these hu-mice showed spontaneous development of B-cell acute lymphoblastic leukemia (B-ALL), which was transplantable to secondary recipients with an autologous human immune system. Using this model, we show that lymphopenia markedly improves the antitumor efficacy of recipient leukocyte infusion (RLI), a GVHD-free immunotherapy that induces antitumor responses in association with rejection of donor chimerism in mixed allogeneic chimeras. Our data demonstrate the potential of this leukemic hu-mouse model in modeling leukemia immunotherapy, and suggest that RLI may offer a safe treatment option for leukemia patients with severe lymphopenia.

Knyazev EN, Samatov TR, Fomicheva KA, et al.
MicroRNA hsa-miR-4674 in Hemolysis-Free Blood Plasma Is Associated with Distant Metastases of Prostatic Cancer.
Bull Exp Biol Med. 2016; 161(1):112-5 [PubMed] Related Publications
We analyzed microRNA profile in hemolysis-free blood plasma of patients with prostatic cancer. The metastatic form of prostatic cancer was found to be associated with increased levels of hsa-miR-22-3p, hsa-miR-663a, and hsa-miR-4674 in comparison with non-metastatic form. Common candidate target genes of these microRNA include JUNB, KMT2A, and XPO6.

Deb P, Bhan A, Hussain I, et al.
Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo.
Gene. 2016; 590(2):234-43 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression. Estrogen-receptors (ERs) and ER-co-regulators such as MLL-histone methylase (MLL3), histone acetylases, CBP/P300, bind to the HOXB9 promoter EREs in the presence of BPA, modify chromatin (histone methylation and acetylation) and lead to gene activation. In summary, our results demonstrate that BPA exposure, like estradiol, increases HOXB9 expression in breast cells both in vitro and in vivo through a mechanism that involves increased recruitment of transcription and chromatin modification factors.

Liu N, Wang C, Wang L, et al.
Valproic acid enhances the antileukemic effect of cytarabine by triggering cell apoptosis.
Int J Mol Med. 2016; 37(6):1686-96 [PubMed] Related Publications
Acute myeloid leukemia (AML) is an aggressive clonal malignancy of hematopoietic progenitor cells with a poor clinical outcome. The resistance of leukemia cells to contemporary chemotherapy is one of the most formidable obstacles to treating AML. Combining valproic acid (VPA) with other anti-leukemic agents has previously been noted as a useful and necessary strategy which can be used to specifically induce anticancer gene expression. In the present study, we demonstrated the synergistic antileukemic activities between VPA and cytarabine (Ara‑C) in a retrovirus-mediated murine model with MLL-AF9 leukemia, three leukemia cell lines (THP-1, K562 and HL-60) and seven primary human AML samples. Using RT-qPCR, we noted that the combination of VPA and Ara‑C significantly upregulated Bax expression and led to the arrest of leukemia cell proliferation, sub-G1 DNA accumulation and cell apoptosis, as demonstrated by flow cytometric analysis. Significantly, further experiments revealed that knockdown of Bax expression prevented VPA and Ara‑C‑induced cell apoptosis in THP-1 cells. The results of our present study demonstrated the synergistic antileukemic effect of combined VPA and Ara‑C treatment in AML, and thus we suggest that VPA be used an alternative treatment for AML.

Gao Y, Gao J, Li M, et al.
Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia.
J Hematol Oncol. 2016; 9:36 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment.
METHODS: The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model.
RESULTS: We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1 (Δ/Δ) AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 (Δ/Δ) AML cells.
CONCLUSIONS: Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.

Sontakke P, Koczula KM, Jaques J, et al.
Hypoxia-Like Signatures Induced by BCR-ABL Potentially Alter the Glutamine Uptake for Maintaining Oxidative Phosphorylation.
PLoS One. 2016; 11(4):e0153226 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
The Warburg effect is probably the most prominent metabolic feature of cancer cells, although little is known about the underlying mechanisms and consequences. Here, we set out to study these features in detail in a number of leukemia backgrounds. The transcriptomes of human CB CD34+ cells transduced with various oncogenes, including BCR-ABL, MLL-AF9, FLT3-ITD, NUP98-HOXA9, STAT5A and KRASG12V were analyzed in detail. Our data indicate that in particular BCR-ABL, KRASG12V and STAT5 could impose hypoxic signaling under normoxic conditions. This coincided with an upregulation of glucose importers SLC2A1/3, hexokinases and HIF1 and 2. NMR-based metabolic profiling was performed in CB CD34+ cells transduced with BCR-ABL versus controls, both cultured under normoxia and hypoxia. Lactate and pyruvate levels were increased in BCR-ABL-expressing cells even under normoxia, coinciding with enhanced glutaminolysis which occurred in an HIF1/2-dependent manner. Expression of the glutamine importer SLC1A5 was increased in BCR-ABL+ cells, coinciding with an increased susceptibility to the glutaminase inhibitor BPTES. Oxygen consumption rates also decreased upon BPTES treatment, indicating a glutamine dependency for oxidative phosphorylation. The current study suggests that BCR-ABL-positive cancer cells make use of enhanced glutamine metabolism to maintain TCA cell cycle activity in glycolytic cells.

Guarnerio J, Bezzi M, Jeong JC, et al.
Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations.
Cell. 2016; 165(2):289-302 [PubMed] Related Publications
Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.

Moorman AV
New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia.
Haematologica. 2016; 101(4):407-16 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease at the genetic level. Chromosomal abnormalities are used as diagnostic, prognostic and predictive biomarkers to provide subtype, outcome and drug response information. t(12;21)/ETV6-RUNX1 and high hyper-diploidy are good-risk prognostic biomarkers whereas KMT2A(MLL) translocations, t(17;19)/TCF3-HLF, haploidy or low hypodiploidy are high-risk biomarkers. t(9;22)/BCR-ABL1 patients require targeted treatment (imatinib/dasatinib), whereas iAMP21 patients achieve better outcomes when treated intensively. High-risk genetic biomarkers are four times more prevalent in adults compared to children. The application of genomic technologies to cases without an established abnormality (B-other) reveals copy number alterations which can be used either individually or in combination as prognostic biomarkers. Transcriptome sequencing studies have identified a network of fusion genes involving kinase genes -ABL1,ABL2,PDGFRB,CSF1R,CRLF2,JAK2 and EPOR in-vitro and in-vivo studies along with emerging clinical observations indicate that patients with a kinase-activating aberration may respond to treatment with small molecular inhibitors like imatinib/dasatinib and ruxolitinib. Further work is required to determine the true frequency of these abnormalities across the age spectrum and the optimal way to incorporate such inhibitors into protocols. In conclusion, genetic biomarkers are playing an increasingly important role in the management of patients with ALL.

Stanley RF, Steidl U
Ectopic DNMT3B expression delays leukemogenesis.
Blood. 2016; 127(12):1525-6 [PubMed] Related Publications
In this issue of Blood, Schulze et al use a tetracycline-inducible Dnmt3b knock-in mouse model to investigate how DNMT3B-mediated DNA methylation affects leukemogenesis. Increased DNMT3B expression prolonged survival in retrovirally induced Myc-Bcl2– or MLL-AF9–driven leukemia, and acute myeloid leukemia (AML) patients with high expression of DNMT3B target genes showed inferior overall survival.

Hasegawa K, Tanaka S, Fujiki F, et al.
Glycosylation Status of CD43 Protein Is Associated with Resistance of Leukemia Cells to CTL-Mediated Cytolysis.
PLoS One. 2016; 11(3):e0152326 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
To improve cancer immunotherapy, it is important to understand how tumor cells counteract immune-surveillance. In this study, we sought to identify cell-surface molecules associated with resistance of leukemia cells to cytotoxic T cell (CTL)-mediated cytolysis. To this end, we first established thousands of monoclonal antibodies (mAbs) that react with MLL/AF9 mouse leukemia cells. Only two of these mAbs, designated R54 and B2, bound preferentially to leukemia cells resistant to cytolysis by a tumor cell antigen-specific CTLs. The antigens recognized by these mAbs were identified by expression cloning as the same protein, CD43, although their binding patterns to subsets of hematopoietic cells differed significantly from each other and from a pre-existing pan-CD43 mAb, S11. The epitopes of R54 and B2, but not S11, were sialidase-sensitive and expressed at various levels on leukemia cells, suggesting that binding of R54 or B2 is associated with the glycosylation status of CD43. R54high leukemia cells, which are likely to express sialic acid-rich CD43, were highly resistant to CTL-mediated cytolysis. In addition, loss of CD43 in leukemia cells or neuraminidase treatment of leukemia cells sensitized leukemia cells to CTL-mediated cell lysis. These results suggest that sialic acid-rich CD43, which harbors multiple sialic acid residues that impart a net negative surface charge, protects leukemia cells from CTL-mediated cell lysis. Furthermore, R54high or B2high leukemia cells preferentially survived in vivo in the presence of adaptive immunity. Taken together, these results suggest that the glycosylation status of CD43 on leukemia is associated with sensitivity to CTL-mediated cytolysis in vitro and in vivo. Thus, regulation of CD43 glycosylation is a potential strategy for enhancing CTL-mediated immunotherapy.

Kim JH, Baddoo MC, Park EY, et al.
SON and Its Alternatively Spliced Isoforms Control MLL Complex-Mediated H3K4me3 and Transcription of Leukemia-Associated Genes.
Mol Cell. 2016; 61(6):859-73 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

Palanichamy JK, Tran TM, Howard JM, et al.
RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation.
J Clin Invest. 2016; 126(4):1495-511 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.

Feng Z, Yao Y, Zhou C, et al.
Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia.
J Hematol Oncol. 2016; 9:24 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
BACKGROUND: Mixed lineage leukemia (MLL) gene translocations are found in ~75% infant and 10% adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed.
METHODS: LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
RESULTS: Potent LSD1 inhibitors with biochemical IC50 values of 9.8-77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC50 of 10-320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis.
CONCLUSIONS: LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.

Getlik M, Smil D, Zepeda-Velázquez C, et al.
Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1).
J Med Chem. 2016; 59(6):2478-96 [PubMed] Related Publications
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp < 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.

Colović N, Bogdanović A, Virijević M, et al.
Acute Myocardial Infarction during Induction Chemotherapy for Acute MLL t(4;11) Leukemia with Lineage Switch and Extreme Leukocytosis.
Srp Arh Celok Lek. 2015 Nov-Dec; 143(11-12):734-8 [PubMed] Related Publications
INTRODUCTION: In patients with acute leukemias hemorrhage is the most frequent problem. Vein thrombotic events may appear rarely but arterial thromboses are exceptionally rare. We present a patient with acute leukemia and bilateral deep leg vein thrombosis who developed an acute myocardial infarction (AMI) during induction chemotherapy. The etiology and treatment of AMI in patients with acute leukemia, which is a rare occurrence, is discussed.
CASE OUTLINE: In April of 2012 a 37-year-old male presented with bilateral deep leg vein thrombosis and malaise. Laboratory data were as follows: Hb 118 g/L, WBC 354 x 10(9)/L (with 91% blasts in differential leukocyte count), platelets 60x109/L. Bone marrow aspirate and immunophenotype revealed the presence of acute lymphoblastic leukemia. Cytogenetic analysis was as follows: 46,XY,t(4;11)(q21:q23) [2]/62-82,XYt(4;11)[18]. Molecular analysis showed MLL-AF4 rearrangement. The patient was on low molecular weight heparin and combined chemotherapy according to protocol HyperCVAD. On day 10 after chemotherapy he got chest pain. Three days later AMI was diagnosed (creatine kinase 66 U/L, CK-MB 13U/L, troponin 1.19 µg/L). Electrocardiogram showed the ST elevation in leads D1, D2, aVL, V5 and V6 and "micro q" in D1. On echocardiography, hypokinesia of the left ventricle and ejection fraction of 39% was found. After recovering from AMI and restoring left ventricle ejection fraction to 59%, second course of HyperCVAD was given. The control bone marrow aspirate showed 88% of blasts but with monoblastic appearance. Flow cytometry confirmed a lineage switch from lymphoblasts to monoblasts. In further course of the disease he was treated with a variety of chemotherapeutic combinations without achieving remission. Eventually, palliative chemotherapy was administered to reduce the bulk of blasts. He died five months after the initial diagnosis.
CONCLUSION: AMI in young adults with acute leukemia is a very rare complication which may occur in patients with very high white blood cell count in addition with presence of a CD56 adhesion molecule and other concomitant thrombophilic factors. The treatment of AMI in patients with acute leukemias should include antiplatelet and anticoagulant therapy, even with more aggressive methods depending on patient's age and clinical risk assessment.

You BR, Park WH
The levels of HDAC1 and thioredoxin1 are related to the death of mesothelioma cells by suberoylanilide hydroxamic acid.
Int J Oncol. 2016; 48(5):2197-204 [PubMed] Related Publications
Mesothelioma is an aggressive tumor which is mainly derived from the pleura of lung. In the present study, we evaluated the anticancer effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor on human mesothelioma cells in relation to the levels of HDAC1, reactive oxygen species (ROS) and thioredoxin (Trx). While 1 µM SAHA inhibited cell growth in Phi and ROB cells at 24 h, it did not affect the growth in ADA and Mill cells. Notably, the level of HDAC1 was relatively overexpressed among Phi, REN and ROB cells. SAHA induced necrosis and apoptosis, which was accompanied by the cleavages of PARP and caspase-3 in Phi cells. This agent also increased the loss of mitochondrial membrane potential (MMP, ΔΨm) in Phi cells. All the tested caspase inhibitors attenuated apoptosis in SAHA-treated Phi cells whereas HDAC1 siRNA enhanced the apoptotic cell death. SAHA increased intracellular ROS levels including O2•- in Phi cells. N-acetyl cysteine (NAC) and vitamin C (Vit.C) significantly reduced the growth inhibition and death of Phi cells caused by SAHA. This drug decreased the mRNA and protein levels of Trx1 in Phi and ROB cells. Furthermore, Trx1 siRNA increased cell death and O2•- level in SAHA-treated Phi cells. In conclusion, SAHA selectively inhibited the growth of Phi and ROB mesothelioma cells, which showed the higher basal level of HDAC1. SAHA-induced Phi cell death was related to oxidative stress and Trx1 levels.

Riedel SS, Haladyna JN, Bezzant M, et al.
MLL1 and DOT1L cooperate with meningioma-1 to induce acute myeloid leukemia.
J Clin Invest. 2016; 126(4):1438-50 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Meningioma-1 (MN1) overexpression is frequently observed in patients with acute myeloid leukemia (AML) and is predictive of poor prognosis. In murine models, forced expression of MN1 in hematopoietic progenitors induces an aggressive myeloid leukemia that is strictly dependent on a defined gene expression program in the cell of origin, which includes the homeobox genes Hoxa9 and Meis1 as key components. Here, we have shown that this program is controlled by two histone methyltransferases, MLL1 and DOT1L, as deletion of either Mll1 or Dot1l in MN1-expressing cells abrogated the cell of origin-derived gene expression program, including the expression of Hoxa cluster genes. In murine models, genetic inactivation of either Mll1 or Dot1l impaired MN1-mediated leukemogenesis. We determined that HOXA9 and MEIS1 are coexpressed with MN1 in a subset of clinical MN1hi leukemia, and human MN1hi/HOXA9hi leukemias were sensitive to pharmacologic inhibition of DOT1L. Together, these data point to DOT1L as a potential therapeutic target in MN1hi AML. In addition, our findings suggest that epigenetic modulation of the interplay between an oncogenic lesion and its cooperating developmental program has therapeutic potential in AML.

Shin MH, He Y, Marrogi E, et al.
A RUNX2-Mediated Epigenetic Regulation of the Survival of p53 Defective Cancer Cells.
PLoS Genet. 2016; 12(2):e1005884 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
The inactivation of p53 creates a major challenge for inducing apoptosis in cancer cells. An attractive strategy is to identify and subsequently target the survival signals in p53 defective cancer cells. Here we uncover a RUNX2-mediated survival signal in p53 defective cancer cells. The inhibition of this signal induces apoptosis in cancer cells but not non-transformed cells. Using the CRISPR technology, we demonstrate that p53 loss enhances the apoptosis caused by RUNX2 knockdown. Mechanistically, RUNX2 provides the survival signal partially through inducing MYC transcription. Cancer cells have high levels of activating histone marks on the MYC locus and concomitant high MYC expression. RUNX2 knockdown decreases the levels of these histone modifications and the recruitment of the Menin/MLL1 (mixed lineage leukemia 1) complex to the MYC locus. Two inhibitors of the Menin/MLL1 complex induce apoptosis in p53 defective cancer cells. Together, we identify a RUNX2-mediated epigenetic mechanism of the survival of p53 defective cancer cells and provide a proof-of-principle that the inhibition of this epigenetic axis is a promising strategy to kill p53 defective cancer cells.

Calderwood SK, Neckers L
Hsp90 in Cancer: Transcriptional Roles in the Nucleus.
Adv Cancer Res. 2016; 129:89-106 [PubMed] Related Publications
Hsp90 plays a key role in fostering metabolic pathways essential in tumorigenesis through its functions as a molecular chaperone. Multiple oncogenic factors in the membrane and cytoplasm are thus protected from degradation and destruction. Here, we have considered Hsp90's role in transcription in the nucleus. Hsp90 functions both in regulating the activity of sequence-specific transcription factors such as nuclear receptors and HSF1, as well as impacting more globally acting factors that act on chromatin and RNA polymerase II. Hsp90 influences transcription by modulating histone modification mediated by its clients SMYD3 and trithorax/MLL, as well as by regulating the processivity of RNA polymerase II through negative elongation factor. It is not currently clear how the transcriptional role of Hsp90 may be influenced by the cancer milieu although recently discovered posttranslational modification of the chaperone may be involved. Dysregulation of Hsp90 may thus influence malignant processes both by modulating the function of specific transcription factors and effects on more globally acting general components of the transcriptional machinery.

Rayes A, McMasters RL, O'Brien MM
Lineage Switch in MLL-Rearranged Infant Leukemia Following CD19-Directed Therapy.
Pediatr Blood Cancer. 2016; 63(6):1113-5 [PubMed] Related Publications
Rearrangements of the mixed lineage leukemia (MLL) gene occur frequently in infants with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Conversions of leukemia cell lineage are rare, but occur most commonly in the setting of MLL-rearrangement. Blinatumomab is a bidirectional antibody targeting CD19 with significant activity in relapsed B-precursor ALL. We report an infant with ALL with t(4;11)(q21;q23) refractory to cytotoxic chemotherapy who was treated with blinatumomab. Following rapid initial clearance of peripheral lymphoblasts, bone marrow evaluation demonstrated a leukemic lineage switch to CD19-negative monoblastic AML. Complete remission was achieved with myeloid-directed chemotherapy.

Zhou C, Zhang Y, Dai J, et al.
Pygo2 functions as a prognostic factor for glioma due to its up-regulation of H3K4me3 and promotion of MLL1/MLL2 complex recruitment.
Sci Rep. 2016; 6:22066 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Pygo2 has been discovered as an important Wnt signaling component contributing to the activation of Wnt-target gene transcription. In the present study, we discovered that Pygo2 mRNA and protein levels were up-regulated in the majority of (152/209) human brain glioma tissues and five glioma cell lines, and significantly correlated with the age, the WHO tumor classification and poor patient survival. The histone methyltransferase complex components (WDR5, Ash2, and menin, but not CXCC1 or NCOA6) were down-regulated at the promoter loci of Wnt target genes after Pygo2 knockdown, and this was accompanied by the down-regulation of Wnt/β-catenin pathway activity. Further, we demonstrated that the involvement of Pygo2 in the activation of the Wnt pathway in human glioma progression is through up-regulation of the H3K4me3 (but not H3K4me2) by promoting the recruitment of the histone methyltransferase MLL1/MLL2 complex to Wnt target gene promoters. Thus, our study provided evidence that Pygo2 functions as a novel prognostic marker and represents a potential therapeutic target.

Yeh CH, Bai XT, Moles R, et al.
Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia.
Mol Cancer. 2016; 15:15 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
BACKGROUND: Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated.
METHOD: Here we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4.
RESULTS: TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells.
CONCLUSIONS: Our results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.

Vera-Aguilera J, Mukarram O, Nutalapati P, et al.
Bilateral orbital myeloid sarcoma preceding acute myeloid leukemia in an adult: a case report and review of the literature.
J Med Case Rep. 2016; 10:31 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
BACKGROUND: Acute myeloid leukemia is typically a disease of the older population and presents mostly in the fifth decade of life. Myeloid sarcoma is a rare initial presentation of acute myeloid leukemia. Previously it has only been documented in children and younger patients.
CASE PRESENTATION: We present an unusual case of retro-orbital myeloid sarcoma as an initial presentation of acute myeloid leukemia in a 43-year-old Caucasian man, with rearrangement of chromosome 11q23 involving the MLL gene.
CONCLUSIONS: We present an unusual case of retro-orbital myeloid sarcoma as an initial presentation of acute myeloid leukemia in a 43-year-old man, with rearrangement of chromosome 11q23 involving the MLL gene.

Prieto C, Stam RW, Agraz-Doblas A, et al.
Activated KRAS Cooperates with MLL-AF4 to Promote Extramedullary Engraftment and Migration of Cord Blood CD34+ HSPC But Is Insufficient to Initiate Leukemia.
Cancer Res. 2016; 76(8):2478-89 [PubMed] Related Publications
The MLL-AF4 (MA4) fusion gene is the genetic hallmark of an aggressive infant pro-B-acute lymphoblastic leukemia (B-ALL). Our understanding of MA4-mediated transformation is very limited. Whole-genome sequencing studies revealed a silent mutational landscape, which contradicts the aggressive clinical outcome of this hematologic malignancy. Only RAS mutations were recurrently detected in patients and found to be associated with poorer outcome. The absence of MA4-driven B-ALL models further questions whether MA4 acts as a single oncogenic driver or requires cooperating mutations to manifest a malignant phenotype. We explored whether KRAS activation cooperates with MA4 to initiate leukemia in cord blood-derived CD34(+) hematopoietic stem/progenitor cells (HSPC). Clonogenic and differentiation/proliferation assays demonstrated that KRAS activation does not cooperate with MA4 to immortalize CD34(+) HSPCs. Intrabone marrow transplantation into immunodeficient mice further showed that MA4 and KRAS(G12V) alone or in combination enhanced hematopoietic repopulation without impairing myeloid-lymphoid differentiation, and that mutated KRAS did not cooperate with MA4 to initiate leukemia. However, KRAS activation enhanced extramedullary hematopoiesis of MA4-expressing cell lines and CD34(+) HSPCs that was associated with leukocytosis and central nervous system infiltration, both hallmarks of infant t(4;11)(+) B-ALL. Transcriptional profiling of MA4-expressing patients supported a cell migration gene signature underlying the mutant KRAS-mediated phenotype. Collectively, our findings demonstrate that KRAS affects the homeostasis of MA4-expressing HSPCs, suggesting that KRAS activation in MA4(+) B-ALL is important for tumor maintenance rather than initiation. Cancer Res; 76(8); 2478-89. ©2016 AACR.

Capell BC, Drake AM, Zhu J, et al.
MLL1 is essential for the senescence-associated secretory phenotype.
Genes Dev. 2016; 30(3):321-36 [PubMed] Article available free on PMC after 17/03/2017 Related Publications
Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces "SASP-like" inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression.

Huang H, Jiang X, Wang J, et al.
Identification of MLL-fusion/MYC⊣miR-26⊣TET1 signaling circuit in MLL-rearranged leukemia.
Cancer Lett. 2016; 372(2):157-65 [PubMed] Article available free on PMC after 28/03/2017 Related Publications
Expression of functionally important genes is often tightly regulated at both transcriptional and post-transcriptional levels. We reported previously that TET1, the founding member of the TET methylcytosine dioxygenase family, plays an essential oncogenic role in MLL-rearranged acute myeloid leukemia (AML), where it is overexpressed owing to MLL-fusion-mediated direct up-regulation at the transcriptional level. Here we show that the overexpression of TET1 in MLL-rearranged AML also relies on the down-regulation of miR-26a, which directly negatively regulates TET1 expression at the post-transcriptional level. Through inhibiting expression of TET1 and its downstream targets, forced expression of miR-26a significantly suppresses the growth/viability of human MLL-rearranged AML cells, and substantially inhibits MLL-fusion-mediated mouse hematopoietic cell transformation and leukemogenesis. Moreover, c-Myc, an oncogenic transcription factor up-regulated in MLL-rearranged AML, mediates the suppression of miR-26a expression at the transcriptional level. Collectively, our data reveal a previously unappreciated signaling pathway involving the MLL-fusion/MYC⊣miR-26a⊣TET1 signaling circuit, in which miR-26a functions as an essential tumor-suppressor mediator and its transcriptional repression is required for the overexpression and oncogenic function of TET1 in MLL-rearranged AML. Thus, restoration of miR-26a expression/function holds therapeutic potential to treat MLL-rearranged AML.

Cheung N, Fung TK, Zeisig BB, et al.
Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia.
Cancer Cell. 2016; 29(1):32-48 [PubMed] Article available free on PMC after 28/03/2017 Related Publications
Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia.

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