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Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators [ChIP-seq]

ABSTRACT: Molecular mechanisms driving clonal aggressiveness in leukemia are not fully understood. We tracked and analyzed MLL-rearranged leukemic clones independently evolving towards higher aggressiveness. More aggressive subclones lost their growth differential ex vivo but restored it upon secondary transplantation, suggesting molecular memory of aggressiveness. Development of aggressiveness was associated with clone-specific gradual modulation of chromatin states and expression levels across the genome, with a surprising preferential trend of reversing the earlier changes between normal and leukemic progenitors. To focus on the core aggressiveness program, we identified genes with consistent changes of expression and chromatin marks that were maintained in vivo and ex vivo in both clones. Overexpressing selected core genes (Smad1 as aggressiveness driver, Irx5 and Plag1 as suppressors) affected leukemic progenitor growth in the predicted way and had convergent downstream effects on central transcription factors and repressive epigenetic modifiers, suggesting a broader regulatory network of leukemic aggressiveness.

ORGANISM(S): Mus musculus

PROVIDER: GSE280195 | GEO | 2026/04/08

REPOSITORIES: GEO

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Project description:Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of immature myeloblasts originating from leukemic stem cells (LSCs) niched within the bone marrow. Bone marrow stromal cells (BMSC) and tumor-stroma interactions play a prominent role in the evolution of this disease. BMSC-mediated protection of leukemic cells involves several mechanisms, including interactions between adhesion molecules, the secretion of cytokines/chemokines and the release of extracellular vesicles produced by the surrounding non-haemopoietic BM cells. Recent studies even suggest that autophagy in the tumor stroma is associated with leukemia progression, survival and resistance. Thus, it seems widely evident that the microenvironment profile affects the prognosis and influences the efficacy of anti-cancer therapies. Yet, although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin (directing endocytosed SDC and receptor cargo back to cell surfaces and/or to endosomal intraluminal vesicles and exosomes) is known to coordinate inter-cellular communications. Using syntenin-knockout mice, we aimed to clarify the role of environmental-syntenin in the progression of AML, a disease in which the role of (tumor/host) syntenin was not yet investigated. To address the role of host-syntenin in AML, I extensively used the mouse FLB1 AML-like model (generous gift of O. Herault, Tours). Strikingly, FLB1 cells show a marked gain in aggressiveness when serially transplanted a syntenin-KO host. This aggressive behavior is cell-autonomous, as not reversed by back transplantation into WT hosts. Moreover, ‘aggressive’ FLB1 blasts, raised by education in a syntenin-negative in vivo background, are able to survive and grow in vitro in the absence of stroma, suggesting the cell-autonomous activation of survival pathways. Surprisingly, this gain of aggressiveness is not accompanied by a noticeable morphotypic or transcriptomic signature. However using quantitative proteomics we highlighted altered mRNA translational control. Aggressive FLB1 show a significant up-regulation of several factors, but most marked for EEF1A2, previously shown to have pro-oncogenic activities in various cancers..Globally, these findings are also consistent with the emerging notion that altered mRNA translational control is a critical factor in cancer development and progression.

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Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators [ChIP-seq]

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