KMT2A

Gene Summary

Gene:KMT2A; lysine (K)-specific methyltransferase 2A
Aliases: HRX, MLL, MLL1, TRX1, ALL-1, CXXC7, HTRX1, MLL1A, WDSTS, MLL-AF9, MLL/GAS7, TET1-MLL
Location:11q23
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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase 2A
HPRD
Source:NCBIAccessed: 27 August, 2015

Ontology:

What does this gene/protein do?
Show (30)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 August 2015 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 27 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (16)

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 Publications115
Acute Lymphocytic Leukaemia (ALL)t(11;19)(q23;p13.1) MLL-ELL translocation in acute leukaemia View Publications17
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
Leukaemiat(10;11)(p11.2;q23) ABI1-MLL translocation in Leukemia View Publications2
Lung CancerKMT2A and Lung Cancer View Publications1
-KMT2A and Residual Disease View Publications2
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)

Angelova S, Spassov B, Nikolova V, et al.
IS THE AMPLIFICATION OF c-MYC, MLL AND RUNX1 GENES IN AML AND MDS PATIENTS WITH TRISOMY 8, 11 AND 21 A FACTOR FOR A CLONAL EVOLUTION IN THEIR KARYOTYPE?
Tsitol Genet. 2015 May-Jun; 49(3):25-32 [PubMed] Related Publications
The aim of our study was 1) to define if the amplification of c-MYC, MLL and RUNX1 genes is related to the progressive changes of the karyotype in patients with AML and MDS with trisomy 8, 11 and 21 (+8, +11 and +21) in bone marrow and 2) can that amplification be accepted as part of the clonal evolution (CE). Karyotype analysis was performed in 179 patients with AML or MDS with the different chromosomal aberrations (CA) aged 16-81. The findings were distributed as follow: initiating balanced CA (n = 60), aneuploidia (n = 55), unbalanced CA (n = 64). Amplification of c-MYC, MLL and RUNX1 genes by means of fluorescence in situ hybridization (FISH) was found in 35% (7 out of 20) of AML and MDS patients with +8, +11 u +21 as single CA in their karyotype; in 63.6% of pts (7 out of 11)--with additional numerical or structural CA and in 75% (9 out of 12)--with complex karyotype. We assume that the amplification of the respective chromosomal regions in patients with +8, +11 and +21 is related to CE. Considering the amplification as a factor of CE, we established 3 patterns of karyotype development depending on the type of the initiating CA in it. Significant statistical differences were found between the three patterns regarding the karyotype distribution in the different stages of progression (p < 0.001).

Rao RC, Dou Y
Hijacked in cancer: the KMT2 (MLL) family of methyltransferases.
Nat Rev Cancer. 2015; 15(6):334-46 [PubMed] Article available free on PMC after 22/05/2016 Related Publications
Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility. Although the human KMT2 family was initially named the mixed-lineage leukaemia (MLL) family, owing to the role of the first-found member KMT2A in this disease, recent exome-sequencing studies revealed KMT2 genes to be among the most frequently mutated genes in many types of human cancers. Efforts to integrate the molecular mechanisms of KMT2 with its roles in tumorigenesis have led to the development of first-generation inhibitors of KMT2 function, which could become novel cancer therapies.

Gill Super HJ
A role for epigenetics in the formation of chromosome translocations in acute leukemia.
Cancer Genet. 2015; 208(5):230-6 [PubMed] Related Publications
In general, the field of cancer genetics seems to have shifted its focus from cancer-associated genes to cancer-associated epigenetic activity. An abundance of evidence suggests that epigenetic malfunction, such as aberrant histone modification, and altered DNA methylation, is at the root of much, if not most aberrant gene expression associated with cancer. However, a role for epigenetics in physical DNA changes, such as chromosome rearrangements, is less obvious, and certainly less well understood. A growing body of evidence suggests that epigenetics may play a role in many of the steps of aberrant chromosome recombination, especially chromosome translocations, associated with cancers such as acute leukemias.

Matveeva E, Kazakova A, Olshanskaya Y, et al.
A new variant of KMT2A(MLL)-FLNA fusion transcript in acute myeloid leukemia with ins(X;11)(q28;q23q23).
Cancer Genet. 2015; 208(4):148-51 [PubMed] Related Publications
The KMT2A gene (previously known as MLL) located at 11q23 is often involved in recurrent chromosomal translocations that lead to the development of acute leukemia, particularly in infants. Acute leukemias with KMT2A rearrangements have different prognoses, which depend on the partner gene involved in the translocation. The detection of all possible types of KMT2A gene rearrangements is of key importance for the identification of biological subgroups, which may differ in clinical outcome. In this report, we describe a case study of a 7-month-old boy who presented with AML-M4; however, no obvious 11q23 rearrangement was detected in the analyzed karyotype. Fluorescence in situ hybridization evaluation showed a nonstandard signal distribution in blast cells, corresponding to the presence of two KMT2A copies and one additional copy of 5'-KMT2A inserted into the long arm of the X chromosome (ins(X;11)(q28;q23q23)). Subsequent molecular analysis showed a novel variant form of the previously described KMT2A-FLNA fusion gene, in which the KMT2A intron 9 is fused to the FLNA exon 16.

Vitali C, Bassani C, Chiodoni C, et al.
SOCS2 Controls Proliferation and Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks Unfavorable Acute Leukemias.
Cancer Res. 2015; 75(11):2387-99 [PubMed] Related Publications
Hematopoietic stem cells (HSC) promptly adapt hematopoiesis to stress conditions, such as infection and cancer, replenishing bone marrow-derived circulating populations, while preserving the stem cell reservoir. SOCS2, a feedback inhibitor of JAK-STAT pathways, is expressed in most primitive HSC and is upregulated in response to STAT5-inducing cytokines. We demonstrate that Socs2 deficiency unleashes HSC proliferation in vitro, sustaining STAT5 phosphorylation in response to IL3, thrombopoietin, and GM-CSF. In vivo, SOCS2 deficiency leads to unrestricted myelopoietic response to 5-fluorouracil (5-FU) and, in turn, induces exhaustion of long-term HSC function along serial bone marrow transplantations. The emerging role of SOCS2 in HSC under stress conditions prompted the investigation of malignant hematopoiesis. High levels of SOCS2 characterize unfavorable subsets of acute myeloid and lymphoblastic leukemias, such as those with MLL and BCR/ABL abnormalities, and correlate with the enrichment of genes belonging to hematopoietic and leukemic stemness signatures. In this setting, SOCS2 and its correlated genes are part of regulatory networks fronted by IKZF1/Ikaros and MEF2C, two transcriptional regulators involved in normal and leukemic hematopoiesis that have never been linked to SOCS2. Accordingly, a comparison of murine wt and Socs2(-/-) HSC gene expression in response to 5-FU revealed a significant overlap with the molecular programs that correlate with SOCS2 expression in leukemias, particularly with the oncogenic pathways and with the IKZF1/Ikaros and MEF2C-predicted targets. Lentiviral gene transduction of murine hematopoietic precursors with Mef2c, but not with Ikzf1, induces Socs2 upregulation, unveiling a direct control exerted by Mef2c over Socs2 expression.

Ney Garcia DR, Liehr T, Emerenciano M, et al.
Molecular studies reveal a MLL-MLLT3 gene fusion displaced in a case of childhood acute lymphoblastic leukemia with complex karyotype.
Cancer Genet. 2015; 208(4):143-7 [PubMed] Related Publications
Rearrangement of the mixed lineage-leukemia gene (MLL-r) is common in hematological diseases and is generally associated with poor prognosis. The mixed-lineage leukemia gene translocated to, 3 (MLLT3) gene (9p22) is a frequent MLL-r partner (∼18% of leukemias with MLL rearrangement) and is characterized by the translocation t(9;11) (p22;q23), forming an MLL-MLLT3 gene fusion. MLL-r are usually simple reciprocal translocations between two different chromosomes, although karyotypes with complex MLL-r have been observed. We present a rare case of a child with acute lymphoblastic leukemia with a complex karyotype in which the classical t(9;11) (p22;q23) was cryptically relocated into a third chromosome in a balanced three-way translocation. At the genome level, however, the MLL-MLLT3 three-way translocation still displayed both reciprocal fusion transcripts. This argues in favor for a model where a simple two-way t(9;11) (p22;q23) was likely the first step that then evolved in to a more complex karyotype. Multicolor banding techniques can be used to greatly refine complex karyotypes and its chromosomal breakpoints. Also in the presence of putative new rearrangements, Long distance inverse-PCR is an important tool to identify which gene fusion is involved.

Kühnl A, Valk PJ, Sanders MA, et al.
Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.
Blood. 2015; 125(19):2985-94 [PubMed] Article available free on PMC after 22/05/2016 Related Publications
The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.

Ford DJ, Dingwall AK
The cancer COMPASS: navigating the functions of MLL complexes in cancer.
Cancer Genet. 2015; 208(5):178-91 [PubMed] Related Publications
The mixed-lineage leukemia family of histone methyltransferases (MLL1-4, or KMT2A-D) were previously linked to cancer through the founding member, MLL1/KMT2A, which is often involved in translocation-associated gene fusion events in childhood leukemias. However, in recent years, a multitude of tumor exome sequencing studies have revealed that orthologues MLL3/KMT2C and MLL2/KMT2D are mutated in a significant percentage of a large variety of malignancies, particularly solid tumors. These unexpected findings necessitate a deeper inspection into the activities and functional differences between the MLL/KMT2 family members. This review provides an overview of this protein family and its relation to cancers, focusing on the recent links between MLL3/KMT2C and MLL2/4/KMT2D and their potential roles as tumor suppressors in an assortment of cell types.

Roychoudhury J, Clark JP, Gracia-Maldonado G, et al.
MEIS1 regulates an HLF-oxidative stress axis in MLL-fusion gene leukemia.
Blood. 2015; 125(16):2544-52 [PubMed] Article available free on PMC after 16/04/2016 Related Publications
Leukemias with MLL translocations are often found in infants and are associated with poor outcomes. The pathogenesis of MLL-fusion leukemias has been linked to upregulation of HOX/MEIS1 genes. The functions of the Hox/Meis1 complex in leukemia, however, remain elusive. Here, we used inducible Meis1-knockout mice coupled with MLL-AF9 knockin mice to decipher the mechanistic role of Meis1 in established MLL leukemia. We demonstrate that Meis1 is essential for maintenance of established leukemia. In addition, in both the murine model and human leukemia cells, we found that Meis1 loss led to increased oxidative stress, oxygen flux, and apoptosis. Gene expression and chromatin immunoprecipitation studies revealed hepatic leukemia factor (HLF) as a target gene of Meis1. Hypoxia or HLF expression reversed the oxidative stress, rescuing leukemia development in Meis1-deficient cells. Thus, the leukemia-promoting properties of Meis1 are at least partly mediated by a low-oxidative state, aided by HLF. These results suggest that stimulants of oxidative metabolism could have therapeutic potential in leukemia treatment.

Andersson AK, Ma J, Wang J, et al.
The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
Nat Genet. 2015; 47(4):330-7 [PubMed] Related Publications
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

Othman MA, Vujić D, Zecević Z, et al.
A cryptic three-way translocation t(10;19;11)(p12.31;q13.31;q23.3) with a derivative Y-chromosome in an infant with acute myeloblastic leukemia (M5b).
Gene. 2015; 563(2):115-9 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant transformation of hematopoietic precursors to a pathogenic cell clone. Chromosomal band 11q23 harboring MLL (=mixed lineage leukemia) gene is known to be involved in rearrangements with variety of genes as activating partners of MLL in different AML subtypes. Overall, an unfavorable prognosis is associated with MLL abnormalities. Here we investigated an 11-month-old male presenting with hyperleukocytosis being diagnosed with AML subtype FAB-M5b. In banding cytogenetics a der(19)t(19;?)(q13.3;?) and del(Y)(q11.23) were found as sole aberrations. Molecular cytogenetics revealed that the MLL gene was disrupted and even partially lost due to a t(10;19;11)(p12.31;q13.31;q23.3), an MLL/MLLT10 fusion appeared, and the der(Y) was an asymmetric inverted duplication with breakpoints in Yp11.2 and Yq11.23. The patient got hematopoietic stem cell transplantation from his haploidentical mother. Still three months afterwards 15% of blasts were detected in bone marrow and later the patient was lost during follow-up. The present case highlights the necessity to exclude MLL rearrangements, even when there seems to be no actual hint from banding cytogenetics.

Othman MA, Grygalewicz B, Pienkowska-Grela B, et al.
Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene.
J Histochem Cytochem. 2015; 63(5):384-90 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP-ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus-specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5' region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL.

Yuan T, Jiao Y, de Jong S, et al.
An integrative multi-scale analysis of the dynamic DNA methylation landscape in aging.
PLoS Genet. 2015; 11(2):e1004996 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Recent studies have demonstrated that the DNA methylome changes with age. This epigenetic drift may have deep implications for cellular differentiation and disease development. However, it remains unclear how much of this drift is functional or caused by underlying changes in cell subtype composition. Moreover, no study has yet comprehensively explored epigenetic drift at different genomic length scales and in relation to regulatory elements. Here we conduct an in-depth analysis of epigenetic drift in blood tissue. We demonstrate that most of the age-associated drift is independent of the increase in the granulocyte to lymphocyte ratio that accompanies aging and that enrichment of age-hypermethylated CpG islands increases upon adjustment for cellular composition. We further find that drift has only a minimal impact on in-cis gene expression, acting primarily to stabilize pre-existing baseline expression levels. By studying epigenetic drift at different genomic length scales, we demonstrate the existence of mega-base scale age-associated hypomethylated blocks, covering approximately 14% of the human genome, and which exhibit preferential hypomethylation in age-matched cancer tissue. Importantly, we demonstrate the feasibility of integrating Illumina 450k DNA methylation with ENCODE data to identify transcription factors with key roles in cellular development and aging. Specifically, we identify REST and regulatory factors of the histone methyltransferase MLL complex, whose function may be disrupted in aging. In summary, most of the epigenetic drift seen in blood is independent of changes in blood cell type composition, and exhibits patterns at different genomic length scales reminiscent of those seen in cancer. Integration of Illumina 450k with appropriate ENCODE data may represent a fruitful approach to identify transcription factors with key roles in aging and disease.

Park SM, Gönen M, Vu L, et al.
Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program.
J Clin Invest. 2015; 125(3):1286-98 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia.

Chen L, Chen W, Mysliwski M, et al.
Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition.
Leukemia. 2015; 29(6):1290-300 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.

Chopra M, Bohlander SK
Disturbing the histone code in leukemia: translocations and mutations affecting histone methyl transferases.
Cancer Genet. 2015; 208(5):192-205 [PubMed] Related Publications
Leukemia is characterized by increased numbers of blasts originating from transformed early hematopoietic stem and progenitor cells. Genetic alterations are widely recognized as the main drivers of oncogenic transformation. Of considerable interest are mutations affecting the writers of epigenetic marks. In this review, we focus on histone methyltransferases--enzymes that catalyze the methylation of lysine residues in core histones. Histone methylation is a tightly controlled mechanism that is responsible for both activating as well as repressing gene expression in a site-specific manner, depending on which lysine residue is methylated. Histone methyltransferases, including MLL1, DOT1L, EZH2, and SETD2 are recurrently deregulated in human leukemia, either directly by gene mutations or balanced translocations, or indirectly as components of protein complexes that are disturbed in leukemia due to alterations of the other components in these complexes. Several small molecule inhibitors of histone methyltransferases are currently being clinically evaluated for their therapeutic potential in human leukemia. These drugs reverse some of the adverse effects of aberrant histone methylation, and can induce differentiation and cell death in leukemic blasts.

Jo A, Mitani S, Shiba N, et al.
High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML.
Leukemia. 2015; 29(5):1076-83 [PubMed] Related Publications
EVI1 and MEL1 are homolog genes whose transcriptional activations by chromosomal translocations are known in small subsets of leukemia. From gene expression profiling data of 130 Japanese pediatric acute myeloid leukemia (AML) patients, we found that EVI1 and MEL1 were overexpressed in ~30% of patients without obvious translocations of these gene loci, and that their high expression was significantly associated with inferior survival. High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype. On the other hand, high MEL1 expression was detected in myelocytic-lineage (designated as e-M0/M1/M2 subtype) and e-M4/M5 subtype leukemia without MLL rearrangements, and its prognostic association was independent from the subtypes. Because of their subtype-dependent and mutually exclusive expression, a combined evaluation of their high expression enabled a clear distinction of patients with inferior survival (P<0.00001 in event-free survival (EFS) and overall survival (OS)). This association was confirmed by quantitative reverse transcription PCR analysis of an independent cohort of 81 patients (P=0.00017 in EFS, P=0.00028 in OS). We propose that the combined estimation of EVI1 and MEL1 expression will be an effective method to predict the prognosis of pediatric AML.

Aoki Y, Watanabe T, Saito Y, et al.
Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.
Blood. 2015; 125(6):967-80 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.

Zhang Y, Peng L, Hu T, et al.
La-related protein 4B maintains murine MLL-AF9 leukemia stem cell self-renewal by regulating cell cycle progression.
Exp Hematol. 2015; 43(4):309-18.e2 [PubMed] Related Publications
Our recent study identified a nonsense mutation of La-related protein 4B (LARP4B) from whole genome sequencing of a 3-year-old female monozygotic twin pair discordant for MLL-associated acute myeloid leukemia (AML). To study the role of LARP4B in AML, we established a LARP4B-knockdown MLL-AF9 AML mouse model. Using this mouse model, we found that LARP4B knockdown significantly decreased leukemia cells in the peripheral blood, spleen, and bone marrow and prolonged the survival of AML recipient mice. Additional studies showed that LARP4B knockdown reduced leukemia stem cells (LSCs) and impaired the self-renew capacity of LSCs. Cell cycle analysis revealed that LARP4B knockdown arrested more LSCs in the G0 phase. The transcription of the cell cycle inhibitors p16, p19, and p21 and of the lineage-specific transcription factor CCAAT-enhancer-binding protein α was increased in the LARP4B-knockdown LSCs. Thus, our results demonstrate that LARP4B plays an important role in the maintenance of LSCs and suggest that LARP4B may regulate the cell cycle of LSCs via suppressing the expression of the cell cycle inhibitors p16, p19, and p21 and the myeloid specific transcription factor CCAAT-enhancer-binding protein α.

Saadatpour A, Guo G, Orkin SH, Yuan GC
Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis.
Genome Biol. 2014; 15(12):525 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: A fundamental challenge for cancer therapy is that each tumor contains a highly heterogeneous cell population whose structure and mechanistic underpinnings remain incompletely understood. Recent advances in single-cell gene expression profiling have created new possibilities to characterize this heterogeneity and to dissect the potential intra-cancer cellular hierarchy.
RESULTS: Here, we apply single-cell analysis to systematically characterize the heterogeneity within leukemic cells using the MLL-AF9 driven mouse model of acute myeloid leukemia. We start with fluorescence-activated cell sorting analysis with seven surface markers, and extend by using a multiplexing quantitative polymerase chain reaction approach to assay the transcriptional profile of a panel of 175 carefully selected genes in leukemic cells at the single-cell level. By employing a set of computational tools we find striking heterogeneity within leukemic cells. Mapping to the normal hematopoietic cellular hierarchy identifies two distinct subtypes of leukemic cells; one similar to granulocyte/monocyte progenitors and the other to macrophage and dendritic cells. Further functional experiments suggest that these subtypes differ in proliferation rates and clonal phenotypes. Finally, co-expression network analysis reveals similarities as well as organizational differences between leukemia and normal granulocyte/monocyte progenitor networks.
CONCLUSIONS: Overall, our single-cell analysis pinpoints previously uncharacterized heterogeneity within leukemic cells and provides new insights into the molecular signatures of acute myeloid leukemia.

Larish AM, Dolan M, Casey T, Perkins JL
Bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement: a novel case in infancy.
J Pediatr Hematol Oncol. 2015; 37(4):e215-7 [PubMed] Related Publications
Mixed-lineage leukemia (MLL) gene rearrangements have rarely been reported in pediatric lymphoma despite their high prevalence in pediatric leukemia. We present a case of an infant with bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement. We also briefly summarize the clinicopathologic significance of MLL gene rearrangements, and review the reported cases of pediatric ovarian lymphoma with and without MLL rearrangement.

Sánchez-Aguilera A, Arranz L, Martín-Pérez D, et al.
Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.
Cell Stem Cell. 2014; 15(6):791-804 [PubMed] Related Publications
Estrogens are potent regulators of mature hematopoietic cells; however, their effects on primitive and malignant hematopoietic cells remain unclear. Using genetic and pharmacological approaches, we observed differential expression and function of estrogen receptors (ERs) in hematopoietic stem cell (HSC) and progenitor subsets. ERα activation with the selective ER modulator (SERM) tamoxifen induced apoptosis in short-term HSCs and multipotent progenitors. In contrast, tamoxifen induced proliferation of quiescent long-term HSCs, altered the expression of self-renewal genes, and compromised hematopoietic reconstitution after myelotoxic stress, which was reversible. In mice, tamoxifen treatment blocked development of JAK2(V617F)-induced myeloproliferative neoplasm in vivo, induced apoptosis of human JAK2(V617F+) HSPCs in a xenograft model, and sensitized MLL-AF9(+) leukemias to chemotherapy. Apoptosis was selectively observed in mutant cells, and tamoxifen treatment only had a minor impact on steady-state hematopoiesis in disease-free animals. Together, these results uncover specific regulation of hematopoietic progenitors by estrogens and potential antileukemic properties of SERMs.

Deshpande AJ, Deshpande A, Sinha AU, et al.
AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.
Cancer Cell. 2014; 26(6):896-908 [PubMed] Article available free on PMC after 08/12/2015 Related Publications
Homeotic (HOX) genes are dysregulated in multiple malignancies, including several AML subtypes. We demonstrate that H3K79 dimethylation (H3K79me2) is converted to monomethylation (H3K79me1) at HOX loci as hematopoietic cells mature, thus coinciding with a decrease in HOX gene expression. We show that H3K79 methyltransferase activity as well as H3K79me1-to-H3K79me2 conversion is regulated by the DOT1L cofactor AF10. AF10 inactivation reverses leukemia-associated epigenetic profiles, precludes abnormal HOXA gene expression, and impairs the transforming ability of MLL-AF9, MLL-AF6, and NUP98-NSD1 fusions-mechanistically distinct HOX-activating oncogenes. Furthermore, NUP98-NSD1-transformed cells are sensitive to small-molecule inhibition of DOT1L. Our findings demonstrate that pharmacological inhibition of the DOT1L/AF10 complex may provide therapeutic benefits in an array of malignancies with abnormal HOXA gene expression.

Ugale A, Norddahl GL, Wahlestedt M, et al.
Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.
Cell Rep. 2014; 9(4):1246-55 [PubMed] Related Publications
Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type. We show that AML can originate from multiple hematopoietic progenitor subsets with granulocytic and monocytic potential, and that the normal developmental position of leukemia-initiating cells influences leukemic development. However, disease failed to arise from HSCs. Although it maintained or upregulated the expression of target genes associated with leukemic development, MLL-ENL dysregulated the proliferative and repopulating capacity of HSCs. Therefore, the permissiveness for development of AML may be associated with a narrower window of differentiation than was previously appreciated, and hijacking the self-renewal capacity of HSCs by a potent oncogene is insufficient for leukemic development.

Dreyer ZE, Hilden JM, Jones TL, et al.
Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3).
Pediatr Blood Cancer. 2015; 62(3):419-26 [PubMed] Related Publications
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS.
PROCEDURE: P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort.
RESULTS: We report an overall 5-year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL-R ALL and white cell count ≥50,000/μl. For infants ≤90 days of age, the 5-year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 ± 8% for MLL-R versus 69.1 ± 13.6% for MLL-germline ALL (P < 0.0001).
CONCLUSIONS: Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL.

Tang G, DiNardo C, Zhang L, et al.
MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation.
Hum Pathol. 2015; 46(1):65-73 [PubMed] Related Publications
MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent -5/del(5q), -18, and -17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course.

Willer A, Jakobsen JS, Ohlsson E, et al.
TGIF1 is a negative regulator of MLL-rearranged acute myeloid leukemia.
Leukemia. 2015; 29(5):1018-31 [PubMed] Related Publications
Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general importance of this family in malignant hematopoiesis, we therefore tested the potential function of TGIF1 in the maintenance of MLL-rearranged AML. Gene expression analysis of MLL-rearranged patient blasts demonstrated reduced TGIF1 levels, and, in accordance, we find that forced expression of TGIF1 in MLL-AF9-transformed cells promoted differentiation and cell cycle exit in vitro, and delayed leukemic onset in vivo. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating with MEIS1-bound regions in a competitive manner and that the MEIS1:TGIF1 ratio influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.

Sandhöfer N, Metzeler KH, Rothenberg M, et al.
Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia.
Leukemia. 2015; 29(4):828-38 [PubMed] Related Publications
In acute myeloid leukemia (AML), several signaling pathways such as the phosphatidylinositol-3-kinase/AKT and the mammalian target of rapamycin (PI3K/AKT/mTOR) pathway are deregulated and constitutively activated as a consequence of genetic and cytogenetic abnormalities. We tested the effectiveness of PI3K/AKT/mTOR-targeting therapies and tried to identify alterations that associate with treatment sensitivity. By analyzing primary samples and cell lines, we observed a wide range of cytotoxic activity for inhibition of AKT (MK-2206), mTORC1 (rapamycin) and PI3K/mTORC1/2 (BEZ-235) with a high sensitivity of cells carrying an MLL rearrangement. In vivo PI3K/mTOR inhibition delayed tumor progression, reduced tumor load and prolonged survival in an MLL-AF9(+)/FLT3-ITD(+) xenograft mouse model. By performing targeted amplicon sequencing in 38 MLL-AF9(+) and 125 cytogenetically normal AML patient samples, we found a high additional mutation rate for genes involved in growth factor signaling in 79% of all MLL-AF9(+) samples, which could lead to a possible benefit of this cohort. PI3K/mTOR inhibition for 24 h led to the cross-activation of the ERK pathway. Further in vitro studies combining PI3K/mTOR and ERK pathway inhibition revealed highly synergistic effects in apoptosis assays. Our data implicate a possible therapeutic benefit of PI3K/mTOR inhibition in the MLL-mutated subgroup. Inhibiting rescue pathways could improve the therapeutic efficacy of PI3K-targeted therapies in AML.

Kim HS, Lim GY, Hwang J, et al.
Induction of apoptosis by obovatol as a novel therapeutic strategy for acute myeloid leukemia.
Int J Mol Med. 2014; 34(6):1675-80 [PubMed] Related Publications
Obovatol, a compound isolated from the bark cortex of Magnolia officinalis (cortex Magnoliae officinalis; M. officinalis), has been studied for use in the treatment of solid cancers. However, the mechanisms of action and the effects of obovatol against acute myeloid leukemia (AML) remain unclear and require further investigation. Therefore, this study was conducted using a human AML cell line (MM6). Obovatol increased pro-apoptotic (Bax) and decreased anti-apoptotic (Bcl-2) protein expression, resulting in caspase-3 and caspase-9 activation measured by caspase-Glo 3/7 assay. Furthermore, obovatol activated the mitogen-activated protein kinase (MAPK) signaling pathway [c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38] and inhibited the activation of the nuclear factor-κB (NF-κB) signaling pathway analyzed by western blot analysis. Taken together, these findings provide evidence that obovatol inhibits cell proliferation in AML and induces apoptosis through the activation of the MAPK pathway in addition to the intrinsic apoptotic pathway. In addition, obovatol suppressed the expression of mixed-lineage leukemia (MLL) target genes by inhibiting the activation of the NF-κB pathway. Therefore, these results suggest that obovatol may have potential for use in the treatment of leukemia.

Sachs Z, LaRue RS, Nguyen HT, et al.
NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.
Blood. 2014; 124(22):3274-83 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12V)). Using computational approaches to explore our gene-expression data sets, we found that NRAS(G12V) enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9- and Myb-dependent leukemia self-renewal gene-expression program. NRAS(G12V) was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS(G12V)-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1(Low) cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12V) withdrawal. NRAS(G12V) maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.

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