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Characterizing the Impact of MLL Fusion Variants and Fusion Partners on Leukemia Plasticity Using a Human CRISPR-Engineered MLL-Rearranged Leukemia Model [RNA-Seq Classical]

ABSTRACT: Acute leukemias involving MLL (KMT2A) rearrangements are aggressive hematologic malignancies associated with poor prognosis. MLL fusions typically involve MLL exons 8-14, with AF4 (AFF1) and AF9 (MLLT3) being frequent partners. To investigate how fusion partners and breakpoint locations influence the disease, we developed a CRISPR/Cas9 model by introducing MLL-AF4 (t(4;11)) or MLL-AF9 (t(9;11)) fusions with MLL breakpoints in intron 9 or 11 into cord blood CD34+ cells. The MLL-rearranged cells showed increased proliferation and stemness, as well as an altered immunophenotype involving the upregulation of AML markers. MLL(intron 9)-AF9 cells engrafted robustly in NSG mice and showed high lineage plasticity, switching from a myeloid to a B-lymphoid identity in vivo. Transcriptomic profiling confirmed the lineage switch and the transcriptomic signature revealed progressive stages of B-cell lineage commitment in individual mice. Our model enables mechanistic studies across MLL fusion variants and may guide the development of targeted therapies for MLL-rearranged leukemias.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311933 | GEO | 2026/03/01

REPOSITORIES: GEO

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Characterizing the Impact of MLL Fusion Variants and Fusion Partners on Leukemia Plasticity Using a Human CRISPR-Engineered MLL-Rearranged Leukemia Model

Project description:Acute leukemias involving MLL (KMT2A) rearrangements are aggressive hematologic malignancies associated with poor prognosis. MLL fusions typically involve MLL exons 8-14, with AF4 (AFF1) and AF9 (MLLT3) being frequent partners. To investigate how fusion partners and breakpoint locations influence the disease, we developed a CRISPR/Cas9 model by introducing MLL-AF4 or MLL-AF9 fusions with MLL breakpoints in intron 9 or 11 into cord blood CD34+ cells. The MLL-rearranged cells showed increased proliferation and stemness, as well as an altered immunophenotype involving the upregulation of AML markers. Transcriptomic profiling revealed breakpoint- and partner-specific gene expression patterns that influence the characteristics of the disease. MLL(intron 9)-AF9 cells engrafted robustly in NSG mice and showed high lineage plasticity, switching from a myeloid to a B-lymphoid identity in vivo. Our model enables mechanistic studies across MLL fusion variants and may guide the development of targeted therapies for MLL-rearranged leukemias.

2026-03-01 | GSE311674 | 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

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.

2017-01-24 | 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

2008-11-04 | GSE12360 | GEO

Genome-wide analysis of H3K79 dimethylation in MLL-AF4 leukemic bone marrow

2008-11-04 | GSE12362 | GEO

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.

2018-04-30 | GSE103947 | GEO

Genome-wide analysis of H3K79 dimethylation in normal and MLL-AF4 leukemic pre-B cells

2008-11-04 | GSE12361 | GEO

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.

2016-11-23 | GSE84116 | GEO

Gene expression induced by DOT1L and Menin inhibition in cell line models of leukemia

Project description:Gene expression upon DOT1L inhibition, or Menin inhibition, or a combination of DOT1L and Menin inhibiting agents, was assessed in several MLL-rearranged human cell lines and a mouse model of MLL-AF9 leukemia. The goal of the study was to explore the mechanisms by which the EPZ0004777 and MI-2-2 chemicals collaborate to induce differentiation and cell death in MLL-AF4 and MLL-AF9 leukemias.

2016-11-14 | GSE63664 | GEO

Genetic deletion or small molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML

Project description:The hematological malignancies classified as Mixed Lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia (AML), here we show that genetic inactivation or small molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein driven transformation. Genome wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small molecule inhibitors in the treatment of leukemias harboring MLL-rearrangements.

2017-07-13 | GSE100820 | GEO

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