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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

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311674 | 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 [RNA-Seq Classical]

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 (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.

2026-03-01 | GSE311933 | GEO

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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

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

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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

MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity

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. 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. Functional investigation of 128 conserved MLL-fusion-interactors identified a specific role for the lysine methyltransferase SETD2 in MLL-leukemia. SETD2 loss caused growth arrest and differentiation of AML cells, and led to increased DNA damage. In addition to its role in H3K36 tri-methylation, SETD2 was required to maintain high H3K79 di-methylation and MLL-AF9 binding to critical target genes, such as Hoxa9. SETD2 loss synergized with pharmacologic inhibition of the H3K79 methyltransferase DOT1L to induce DNA damage, growth arrest, differentiation and apoptosis. These results uncover a dependency for SETD2 during MLL-leukemogenesis, revealing a novel actionable vulnerability in this disease.

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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.

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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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