42 results match your criteria surface kmt2a

Mature B cell acute lymphoblastic leukaemia with KMT2A-MLLT3 transcripts in children: three case reports and literature reviews.

Orphanet J Rare Dis 2021 07 30;16(1):331. Epub 2021 Jul 30.

Division of Haematology and Oncology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, People's Republic of China.

Background: Mature B cell acute lymphoblastic leukaemia (BAL) is characterised by French-American-British (FAB)-L3 morphology and the presence of surface immunoglobulin (sIgM) light chain restriction. BAL is also considered as the leukaemic phase of Burkitt lymphoma (BL), in which t (8; 14) (q24; q32) or its variants are related to the myelocytomatosis oncogene (MYC) rearrangement (MYCr) is usually present. However, BAL with lysine methyltransferase 2A (KMT2A, previously called Mixed lineage leukaemia, MLL) gene rearrangement (KMT2Ar, previously called MLLr) is rare. Read More

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Novel germline mutation KMT2A G3131S confers genetic susceptibility to familial myeloproliferative neoplasms.

Ann Hematol 2021 Sep 6;100(9):2229-2240. Epub 2021 Jul 6.

Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.

The current study analyzed the clinical and genetic characteristics of a family with familial myeloproliferative neoplasms (MPNs). Whole-exome sequencing was conducted, and a germline heterozygous mutation in lysine methyltransferase 2A (KMT2A, also known as MLL1), G3131S (c.9391G > A, p. Read More

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September 2021

Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia.

Blood Adv 2021 05;5(9):2350-2361

Fred Hutchinson Cancer Research Center, Seattle, WA.

In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077. Read More

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Is acute lymphoblastic leukemia with mature B-cell phenotype and rearrangements a new entity? A systematic review and meta-analysis.

Leuk Lymphoma 2021 Apr 7:1-9. Epub 2021 Apr 7.

Hematology Service, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

The association between mature B-cell phenotype and rearrangements in acute lymphoblastic leukemia is a very rare finding. It identifies a group of patients with similar clinical and biological characteristics that clearly differs from the entity B-cell lymphoblastic leukemia/lymphoma with t(v;11q23)/rearranged, which typically presents an immature pro B-cell phenotype. We describe the clinical-biological characteristics and disease outcome of three pediatric ALL patients with these features treated at our institution, and review 28 cases described in the literature. Read More

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Surface Proteomics Reveals CD72 as a Target for -Evolved Nanobody-Based CAR-T Cells in -Rearranged B-ALL.

Cancer Discov 2021 Aug 16;11(8):2032-2049. Epub 2021 Mar 16.

Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.

Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis /-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Read More

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Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia.

Genes Chromosomes Cancer 2021 02 20;60(2):88-99. Epub 2020 Nov 20.

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

It has long been known that there is a link between neuron glial antigen 2 (NG2) surface expression and KMT2A gene rearrangements in acute leukemia (AL). However, the exact levels of NG2 positivity that predict the presence of KMT2A rearrangement are not known. The current study focuses on a cohort of 505 pediatric AL patients who showed any level of positive NG2 expression (greater than 1% of cells) for whom comprehensive genetic data were available. Read More

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February 2021

CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy.

Blood 2021 02;137(8):1037-1049

Dr von Hauner Children's Hospital, University Hospital, and.

Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML. Read More

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February 2021

High-fat diet intensifies MLL-AF9-induced acute myeloid leukemia through activation of the FLT3 signaling in mouse primitive hematopoietic cells.

Sci Rep 2020 09 30;10(1):16187. Epub 2020 Sep 30.

Inserm UMR1231, Université Bourgogne Franche-Comté, Dijon, France.

Using a MLL-AF9 knock-in mouse model, we discovered that consumption of a high-fat diet (HFD) accelerates the risk of developing acute myeloid leukemia (AML). This regimen increases the clusterization of FLT3 within lipid rafts on the cell surface of primitive hematopoietic cells, which overactivates this receptor as well as the downstream JAK/STAT signaling known to enhance the transformation of MLL-AF9 knock-in cells. Treatment of mice on a HFD with Quizartinib, a potent inhibitor of FLT3 phosphorylation, inhibits the JAK3/STAT3, signaling and finally antagonizes the accelerated development of AML that occurred following the HFD regimen. Read More

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September 2020

Cryo-EM structure of the human MLL1 core complex bound to the nucleosome.

Nat Commun 2019 12 5;10(1):5540. Epub 2019 Dec 5.

Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, 48109, USA.

Mixed lineage leukemia (MLL) family histone methyltransferases are enzymes that deposit histone H3 Lys4 (K4) mono-/di-/tri-methylation and regulate gene expression in mammals. Despite extensive structural and biochemical studies, the molecular mechanisms whereby the MLL complexes recognize histone H3K4 within nucleosome core particles (NCPs) remain unclear. Here we report the single-particle cryo-electron microscopy (cryo-EM) structure of the NCP-bound human MLL1 core complex. Read More

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December 2019

High-efficiency CRISPR induction of t(9;11) chromosomal translocations and acute leukemias in human blood stem cells.

Blood Adv 2019 10;3(19):2825-2835

Department of Pathology.

Chromosomal rearrangements involving the mixed lineage leukemia () gene, also known as , are often observed in human leukemias and are generally associated with a poor prognosis. To model these leukemias, we applied clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce chromosomal rearrangements in human hematopoietic stem and progenitor cells purified from umbilical cord blood. Electroporation of ribonucleoprotein complexes containing chemically modified synthetic single guide RNAs and purified Cas9 protein induced translocations between chromosomes 9 and 11 [t(9;11)] at an efficiency >1%. Read More

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October 2019

Structural and mechanistic insights into the interaction of the circadian transcription factor BMAL1 with the KIX domain of the CREB-binding protein.

J Biol Chem 2019 11 12;294(45):16604-16619. Epub 2019 Sep 12.

Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany

The mammalian CLOCK:BMAL1 transcription factor complex and its coactivators CREB-binding protein (CBP)/p300 and mixed-lineage leukemia 1 (MLL1) critically regulate circadian transcription and chromatin modification. Circadian oscillations are regulated by interactions of BMAL1's C-terminal transactivation domain (TAD) with the KIX domain of CBP/p300 (activating) and with the clock protein CRY1 (repressing) as well as by the BMAL1 G-region preceding the TAD. Circadian acetylation of Lys within the G-region enhances repressive BMAL1-TAD-CRY1 interactions. Read More

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November 2019

Functional diversity of inhibitors tackling the differentiation blockage of MLL-rearranged leukemia.

J Hematol Oncol 2019 06 28;12(1):66. Epub 2019 Jun 28.

Pharmaceuticals, Research & Development, Bayer AG, Muellerstrasse 178, 13353, Berlin, Germany.

Introduction: The chromosomal rearrangements of the mixed-lineage leukemia gene MLL (KMT2A) have been extensively characterized as a potent oncogenic driver in leukemia. For its oncogenic function, most MLL-fusion proteins exploit the multienzyme super elongation complex leading to elevated expression of MLL target genes. High expression of MLL target genes overwrites the normal hematopoietic differentiation program, resulting in undifferentiated blasts characterized by the capacity to self-renew. Read More

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Myeloid Sarcoma of the Testis in Children: Clinicopathologic and Immunohistochemical Characteristics With KMT2A (MLL) Gene Rearrangement Correlation.

Appl Immunohistochem Mol Morphol 2020 08;28(7):501-507

Department of Pathology, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN.

Myeloid sarcoma (MS) is defined as an extramedullary mass-forming lesion composed of immature myeloid cells. It is a rare but well-known manifestation of acute myeloid leukemia. Pediatrics testicular MS may pose a possible diagnostic challenge, an issue that is underscored in the few testicular pediatric MS cases reported in the literature. Read More

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Guiding COMPASS: Dpy-30 Positions SET1/MLL Epigenetic Signaling.

Structure 2018 12;26(12):1567-1570

Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address:

In this issue of Structure, Haddad et al. (2018) solve the high-resolution trimeric crystal structure of human COMPASS-like components Dpy-30 and Ash2L (2:1) to unravel an uncharacterized interaction surface required for competent H3K4 methylation in cells and clarify Dpy-30's role in the allosteric regulation of KMT2 enzymes. Read More

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December 2018

leukemia induction by t(9;11) chromosomal translocation in human hematopoietic stem cells using genome editing.

Blood Adv 2018 04;2(8):832-845

Department of Pathology, Stanford University, Stanford, CA.

Genome editing provides a potential approach to model de novo leukemogenesis in primary human hematopoietic stem and progenitor cells (HSPCs) through induction of chromosomal translocations by targeted DNA double-strand breaks. However, very low efficiency of translocations and lack of markers for translocated cells serve as barriers to their characterization and model development. Here, we used transcription activator-like effector nucleases to generate t(9;11) chromosomal translocations encoding and reciprocal fusion products in CD34 human cord blood cells. Read More

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Disease Characteristics and Prognostic Implications of Cell-Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Clin Cancer Res 2017 Jul 20;23(14):3649-3656. Epub 2017 Jan 20.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML. Read More

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Characterization of CD22 expression in acute lymphoblastic leukemia.

Pediatr Blood Cancer 2015 Jun 1;62(6):964-9. Epub 2015 Mar 1.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland.

Background: CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL).

Procedure: Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL.

Results: CD22 expression was demonstrated in all subjects (n = 163) with detection on at least 90% of blasts in 155 cases. Read More

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A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation.

Genes Dev 2015 Jan;29(2):123-8

Department of Biochemistry, Microbiology, and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;

The methyltransferase activity of the trithorax group (TrxG) protein MLL1 found within its COMPASS (complex associated with SET1)-like complex is allosterically regulated by a four-subunit complex composed of WDR5, RbBP5, Ash2L, and DPY30 (also referred to as WRAD). We report structural evidence showing that in WRAD, a concave surface of the Ash2L SPIa and ryanodine receptor (SPRY) domain binds to a cluster of acidic residues, referred to as the D/E box, in RbBP5. Mutational analysis shows that residues forming the Ash2L/RbBP5 interface are important for heterodimer formation, stimulation of MLL1 catalytic activity, and erythroid cell terminal differentiation. Read More

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January 2015

A non-active-site SET domain surface crucial for the interaction of MLL1 and the RbBP5/Ash2L heterodimer within MLL family core complexes.

J Mol Biol 2014 Jun 27;426(12):2283-99. Epub 2014 Mar 27.

Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Electronic address:

The mixed lineage leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1-MLL4 and SETd1a,b. Dimethylation of H3K4 requires a sub-complex including WRAD (WDR5, RbBP5, Ash2L, and DPY-30), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL1 SET domain. Read More

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Targeting recruitment of disruptor of telomeric silencing 1-like (DOT1L): characterizing the interactions between DOT1L and mixed lineage leukemia (MLL) fusion proteins.

J Biol Chem 2013 Oct 1;288(42):30585-30596. Epub 2013 Sep 1.

From the Department of Pathology and; the Chemical Biology Doctoral Program, University of Michigan Medical School, Ann Arbor, Michigan 48109 and. Electronic address:

The MLL fusion proteins, AF9 and ENL, activate target genes in part via recruitment of the histone methyltransferase DOT1L (disruptor of telomeric silencing 1-like). Here we report biochemical, biophysical, and functional characterization of the interaction between DOT1L and MLL fusion proteins, AF9/ENL. The AF9/ENL-binding site in human DOT1L was mapped, and the interaction site was identified to a 10-amino acid region (DOT1L865-874). Read More

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October 2013

Antibody-dependent cell-mediated cytotoxicity overcomes NK cell resistance in MLL-rearranged leukemia expressing inhibitory KIR ligands but not activating ligands.

Clin Cancer Res 2012 Nov 26;18(22):6296-305. Epub 2012 Sep 26.

Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.

Purpose: Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)-mediated inhibition. Read More

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November 2012

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.

Nature 2012 Feb 12;482(7386):542-6. Epub 2012 Feb 12.

Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Read More

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February 2012

MLL-ENL leukemia burden initiated in femoral diaphysis and preceded by mature B-cell depletion.

Haematologica 2011 Dec 20;96(12):1770-8. Epub 2011 Sep 20.

CEA, iRCM, Laboratoire de recherche sur la, Réparation et la Transcription dans les cellules Souches, Fontenay-aux-Roses cedex, France.

Background: Molecular and cellular events that resulted in leukemia development are well characterized but initial engraftment and proliferation of leukemic cells in bone marrow and early modifications of the bone marrow microenvironment induced by engrafted leukemic cells remain to be clarified.

Design And Methods: After retro-orbital injection of 1,000 leukemic cells expressing Mixed Lineage Leukemia-Eleven Nineteen Leukemia fusion protein in non-conditioned syngenic mice, kinetics of leukemic burden and alterations of femoral hematopoietic populations were followed using an in vivo confocal imaging system and flow cytometry.

Results: Three days after injection, 5% of leukemic cells were found in femurs. Read More

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December 2011

MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1.

Clin Cancer Res 2010 Apr 23;16(7):2122-30. Epub 2010 Mar 23.

Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Pathology, Brigham & Women's Hospital,75 Francis Street, Boston, MA, 02115, USA.

Purpose: Patients with mixed lineage leukemia (MLL)-rearranged B-lymphoblastic leukemias (B-ALL) have an unfavorable prognosis and require intensified treatment. Multiple MLL fusion partners have been identified, complicating the diagnostic evaluation of MLL rearrangements. We analyzed molecular markers of MLL rearrangement for use in rapid diagnostic assays and found the immunomodulatory protein, Galectin-1 (Gal-1), to be selectively expressed in MLL-rearranged B-ALL. Read More

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Anthracycline dose intensification in acute myeloid leukemia.

N Engl J Med 2009 Sep;361(13):1249-59

Department of Blood and Marrow Transplantation, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.

Background: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival.

Methods: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Read More

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September 2009

WDR5 interacts with mixed lineage leukemia (MLL) protein via the histone H3-binding pocket.

J Biol Chem 2008 Dec 7;283(50):35258-64. Epub 2008 Oct 7.

Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

WDR5 is a component of the mixed lineage leukemia (MLL) complex, which methylates lysine 4 of histone H3, and was identified as a methylated Lys-4 histone H3-binding protein. Here, we present a crystal structure of WDR5 bound to an MLL peptide. Surprisingly, we find that WDR5 utilizes the same pocket shown to bind histone H3 for this MLL interaction. Read More

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December 2008

ALL1 fusion proteins induce deregulation of EphA7 and ERK phosphorylation in human acute leukemias.

Proc Natl Acad Sci U S A 2007 Sep 28;104(36):14442-7. Epub 2007 Aug 28.

Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.

Erythropoietin-producing hepatoma-amplified sequence (Eph) receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, function as a unique signaling system triggered by cell-to-cell interaction and have been shown to mediate neurodevelopmental processes. In addition, recent studies showed deregulation of some of Eph/ephrin genes in human malignancies, suggesting the involvement of this signaling pathway in tumorigenesis. The ALL1 (also termed MLL) gene on human chromosome 11q23 was isolated by virtue of its involvement in recurrent chromosome translocations associated with acute leukemias with poor prognosis. Read More

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September 2007

Molecular characterization of HTLV-1 Tax interaction with the KIX domain of CBP/p300.

J Mol Biol 2007 Sep 29;372(4):958-969. Epub 2007 Jun 29.

Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA. Electronic address:

The viral oncoprotein Tax mediates transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1). Both Tax and the cellular transcription factor CREB bind to viral cyclic AMP response elements (vCREs) located in the viral promoter. Tax and serine 133 phosphorylated CREB (pCREB) bound to the HTLV-1 promoter facilitate viral transcription via the recruitment of the large cellular coactivators CBP/p300. Read More

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September 2007

Establishment of a novel childhood acute myeloid leukaemia cell line, KOPM-88, containing partial tandem duplication of the MLL gene and an in vivo model for childhood acute myeloid leukaemia using NOD/SCID mice.

Br J Haematol 2007 May;137(3):221-32

Department of Pediatrics, and Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

MLL gene rearrangement is common in both adult and childhood acute myeloid leukaemia (AML), and its role in oncogenesis has been investigated. While over 50 translocated-partner genes have been identified so far, few studies have detailed the molecular mechanism of partial tandem duplication (PTD) of the MLL gene. The prognostic impact and contribution to leukaemogenesis of MLL-PTD, especially in childhood cases, remain unknown. Read More

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Resistance of infant leukemia with MLL rearrangement to tumor necrosis factor-related apoptosis-inducing ligand: a possible mechanism for poor sensitivity to antitumor immunity.

Leukemia 2006 Dec 26;20(12):2119-29. Epub 2006 Oct 26.

Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.

Malignant cells generally acquire some immune escape mechanisms for clonal expansion. Immune escape mechanisms also contribute to the failure of graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo-SCT). Infant leukemias with mixed-lineage leukemia (MLL) rearrangement have a remarkably short latency, and GVL effect after allo-SCT has not been clearly evidenced in these leukemias. Read More

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December 2006