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Omics score: 171

A faithful in vivo model of human MLL-AF4 proB acute lymphoblastic leukemia

ABSTRACT: Transcriptome analysis by RNAseq of leukemia model promoted by MLL-Af4 or MLL-AF9 fusion proteins. We find each fusion protein promotes a specific gene signature correlating to those identified in patients Overall design: Human CD34+ hematopoietic stem and progenitor cells were transduced with retrovirus expressing MLL-Af4 or MLL-AF9. Transduced cells were transplanted into immunodeficient mice to induce lymphoid leukemia or placed in myeloid in vitro culture. CD19+ lymphoid leukemia cells (3 AF9, 6 Af4), control health CD19+CD34+ proB cells (n=3) and 4 pairs of Af4 and AF9 CD33+CD19- myeloid culture cells were collected for RNA-seq

INSTRUMENT(S): Illumina HiSeq 1000 (Homo sapiens)

SUBMITTER: Shan Lin

PROVIDER: GSE76978 | GEO | 2016-11-23

SECONDARY ACCESSION(S): PRJNA309171

REPOSITORIES: GEO

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Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.

Lin Shan S Luo Roger T RT Ptasinska Anetta A Kerry Jon J Assi Salam A SA Wunderlich Mark M Imamura Toshihiko T Kaberlein Joseph J JJ Rayes Ahmad A Althoff Mark J MJ Anastasi John J O'Brien Maureen M MM Meetei Amom Ruhikanta AR Milne Thomas A TA Bonifer Constanze C Mulloy James C JC Thirman Michael J MJ

Cancer cell 20161101 5

The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic ...[more]

PMID: 27846391

Similar Datasets

Instructive role of MLL fusion proteins revealed by a faithful model of t(4;11) proB acute lymphoblastic leukemia

Project description:The t(4;11)(q21;q23) fuses MLL to AF4, the most common MLL fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34+ cells to generate a faithful model of t(4;11) proB ALL that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a distinct B-ALL from MLL-AF9 through differential DNA binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. We observed this incongruity in t(4;11) patients who evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis. Overall design: MLL-AF4 ChIP-seq expreiment has been used in this study

| GSE84116 | GEO

Protein Interactions of 7 MLL-fusion Proteins

Project description:MLL-fusions represent a large group of leukemia drivers, whose diversity originates from the vast molecular heterogeneity of C-terminal fusion partners of MLL protein. While studies of selected MLL-fusions have revealed critical molecular pathways, unifying mechanisms across all MLL-fusions remain poorly understood. We present the first comprehensive survey of protein-protein interactions of seven distantly related MLL-fusion proteins: MLL-AF1p, MLL-AF4, MLL-AF9, MLL-CBP, MLL-EEN, MLL-ENL and MLL-GAS7.

2018-05-25 | PXD009338 | Pride

Fusion partner directed chromatin occupancy drives the transcriptome heterogeneity of MLL-fusion acute lymphoblastic leukemia

Project description:Fusion of the N-terminus of the mixed-lineage-leukemia (MLL) gene with various partner genes drives acute lymphoblastic leukemia (ALL). Despite the fusion proteins sharing some common attributes, transcriptome heterogeneity of MLL-fusion ALL is observed and the underlying mechanism and biological consequences are unknown. We compared the genome-wide occupancy of MLL-Af4 and MLL-AF9 in human ALL cells expressing FLAG-tagged fusion proteins. Although both oncoproteins retain the same MLL N-terminal domains that mediate chromatin binding, the two fusion proteins displayed largely non-overlapping binding profiles, with MLL-AF9 showing preferential binding at repetitive elements. The binding specificity of each fusion protein was associated with differential global gene activation distinguishing the two ALLs. A subset of prednisolone response genes were among the differentially regulated targets, and the resistance related genes were specifically upregulated in MLL-Af4/AF4 cells. These studies provide evidence that distinct chromatin occupancy of different MLL-fusion proteins is one driving force for transcriptome heterogeneity of MLL-fusion ALL, which could potentially result in the disparate therapeutic outcome of the disease. Overall design: MLL-AF9 ChIP-seq expreiment has been used in this study

| GSE103947 | GEO

Expression data from infant ALL with MLL-AF4 rearrangement

Project description:MLL-AF4+ blasts from infant B-ALL, CB-derived CD34+CD38-CD19-CD33- HSC, CB-derived CD34+CD19+CD33- B-cell HPCs and CB-derived CD34+CD33+CD19- myeloid HPCs. We used microarray to estudy gene expression profile comparing ALL vs HSC, HPC and myeloid HPSC. We used highly FACS-purified (purity>98%) MLL-AF4+ blasts from infant B-ALL, CB-derived CD34+CD38-CD19-CD33- HSC, CB-derived CD34+CD19+CD33- B-cell HPCs and CB-derived CD34+CD33+CD19- myeloid HPCs. For each independent sample technical duplicates were always performed. Total RNA was extracted using TRIol reagent, and quantified on a Nanodrop spectrophotometer and Bioanalyzer. High-quality RNA was reverse transcribed and the obtained cDNA was used as a template to synthesize biotinylanted cDNA, then was fragmented and hybridized as duplicates/triplicates to HG-U133 plus2.0 GeneChips (Affymetrix) according to manufacturer's guideline.

2016-03-22 | E-GEOD-79450 | ArrayExpress

The MLL-AF9 and MLL-AF4 oncofusion proteins bind a distinct enhancer repertoire and target the RUNX1 program in MLLr AML

Project description:In MLL-rearranged (MLLr) leukemias the N terminal part of the MLL gene can be fused to over 60 different partner genes. Here, we investigate the genome wide binding of the MLL-AF9 and MLL-AF4 fusion proteins and their epigenetic signatures in order to define a core set of MLLr targets. We uncover both common as well as specific MLL-AF9 and MLL-AF4 target genes, which are all marked by H3K79me2, H3K27ac, and H3K4me3. Apart from promoter binding, we also identify MLL-AF9 and MLL-AF4 binding at specific subsets of non overlapping active distal regulatory elements. Despite this differential enhancer binding MLL-AF9 and MLL-AF4 still share a common gene program, which represents part of the RUNX1 gene program and constitutes of CD34+ and monocyte specific genes. Comparing these datasets revealed several zinc finger transcription factors as potential MLL-AF9 co-regulators. Together these results suggest that MLL-fusions collaborate with specific subsets of TFs to aberrantly regulate the RUNX1 gene program in 11q23 AMLs. Overall design: Genome-wide (ChIP-seq) binding of MLL, AF9, AF4, H3K4me3, H3K27ac, H3K79me2 and RUNX1 in THP-1 and MV4-11 AML cell lines. Expression Profiling (RNA-seq) of THP-1 and MV4-11 cell lines, as well as 5 MLL-AF9 positive patient blasts.

| GSE79899 | GEO

Genome-wide analysis of H3K79 methylation in CD34+ CD19+ cells from normal marrow, MLL-rearranged or MLL-germline ALL

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). ChIP-chip analysis demonstrated increased histone H3 Lysine 79 (H3K79) dimethylation that correlated with Mll-AF4 associated gene expression profiles in murine ALLs, and in human MLL-rearranged leukemias. In addition, human MLL-rearranged ALLs can be distinguished from other ALLs by their genome-wide H3K79 methylation profiles. Keywords: Cell type comparison Overall design: DNA immunoprecipitated with anti-dimethyl-H3K79 antibodies from normal CD34+CD19+ cells, leukemic bone marrow from MLL-rearranged ALL or MLL-germline ALL was hybridized to Affymetrix promoter tiling microarrays.

| GSE12360 | GEO

Transcription profiling of mouse activated or control 5-FU bone marrow from MLL-AF4stop knockins

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. To examine early, pre-leukemic changes in lymphoid cells due to Mll-AF4 expression, we infected 5-FU bone marrow cells from Mll-AF4stop knocking mice with activating (Cre-GFP) or control (MIF-GFP) retrovirus ex vivo and measured expression changes after culture under lymphoid growth conditions. Experiment Overall Design: Mll-AF4stop knock-in mice were treated with 5-FU and 5 days later their bone marrow infected ex vivo with either Cre-GFP to activate the Mll-AF4 fusion construct or with a control MIG-Cre retrovirus. GFP+ cells were sorted 2 days post-infection and cultured for 14 days under lymphoid growth conditions before total RNA was isolated for hybridization to Affymetrix expression microarrays.

2008-11-13 | E-GEOD-12313 | ArrayExpress

Expression profiling of activated or control 5-FU bone marrow from MLL-AF4stop knockin mice

Project description:We created a mouse model where conditional expression of physiologic levels of an Mll-AF4 fusion oncogene induces development of acute lymphoblastic (ALL) or acute myeloid leukemias (AML). Immunophenotypic and gene expression analysis of the ALL cells demonstrated bone marrow replacement with B-precursor cells which express a gene expression profile that has significant overlap with profiles in human MLL-rearranged ALL. To examine early, pre-leukemic changes in lymphoid cells due to Mll-AF4 expression, we infected 5-FU bone marrow cells from Mll-AF4stop knocking mice with activating (Cre-GFP) or control (MIF-GFP) retrovirus ex vivo and measured expression changes after culture under lymphoid growth conditions. Keywords: Cell type comparison Overall design: Mll-AF4stop knock-in mice were treated with 5-FU and 5 days later their bone marrow infected ex vivo with either Cre-GFP to activate the Mll-AF4 fusion construct or with a control MIG-Cre retrovirus. GFP+ cells were sorted 2 days post-infection and cultured for 14 days under lymphoid growth conditions before total RNA was isolated for hybridization to Affymetrix expression microarrays.

2008-11-04 | GSE12313 | GEO

Zinc finger protein 521 overexpression is a feature of MLL-rearranged acute myeloid leukemia and contributes to the maintenance of myeloid differentiation block

Project description:ZNF521 is a multiple zinc finger transcription factor previously identified because abundantly and selectively expressed in normal CD34+ hematopoietic stem and progenitor cells. From microarray datasets, aberrant expression of ZNF521 has been reported in both pediatric and adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. However, a proper validation of microarray data is lacking, likewise ZNF521 contribution in MLL-rearranged AML is still uncertain. In this study, we show that ZNF521 is significantly upregulated in MLL translocated AML patients from a large pediatric cohort, regardless of the type of MLL translocations such as MLL-AF9, MLL-ENL, MLL-AF10 and MLL-AF6 fusion genes. Our in vitro functional studies demonstrate that ZNF521 play a critical role in the maintenance of the undifferentiated state of MLL-rearranged cells. Furthermore, analysis of the ZNF521 gene promoter region shows that ZNF521 is a direct downstream target of both MLL-AF9 and MLL-ENL fusion proteins. Gene expression profiling of MLL-AF9-rearranged THP-1 cells after depletion of ZNF521 reveals correlation with several expression signatures including stem cell-like and MLL fusion dependent programs. These data suggest that MLL fusion proteins activate ZNF521 expression to maintain the undifferentiated state and contribute to leukemogenesis. ZNF521 is required to block differentiation in MLL-rearranged AML cells Overall design: Gene expression was measured on Affymetrix in 3 independent experiments of THP-1 cells transfected with Lentiviral shRNA vector against ZNF521 (shZNF521) or control scrambled shRNA (shScram)

| GSE79110 | GEO

Genes regulated by Meis1 in murine Mll-AF9 leukemia cells

Project description:Leukemias with MLL-rearrangements are characterized by high expression of the homeo box gene MEIS1. In these studies, we knocked down Meis1 expression by shRNA lentivirus transduction in murine Mll-AF9 leukemia cells. Meis1 knockdown resulted in decreased proliferation and survival of murine Mll-AF9 leukemia cells. We also observed reduced clonogenic capacity and increased monocytic differentiation. The establishment of leukemia in transplant recipients was significantly delayed by Meis1 knockdown. Gene expression profiling of cells transduced with Meis1 shRNA showed reduced expression of genes associated with cell cycle entry and progression. shRNA mediated knockdown of MEIS1 in human MLL-fusion gene leukemia cell lines resulted in reduced cell growth. These results show that MEIS1 expression is important for MLL-rearranged leukemias and suggest that MEIS1 promotes cell cycle entry. Targeting MEIS1 may have therapeutic potential for treating leukemias expressing this transcription factor. Keywords: Gene expression Overall design: Murine Mll-AF9 leukemia (4166) cells were transduced with lentivirus expressing shRNA against Meis1 or control lentivirus (empty vector). Gene expression profiles were compared at 48 hours post transduction, using Puromycin as selection agent for transduced cells.

2008-12-23 | GSE14101 | GEO

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