Dataset Information

An intronic region within FTO confers differentiation block in acute myeloid leukaemia through regulation of IRX3 and HOX [MeDIP-seq re-analyzed]

ABSTRACT: In acute myeloid leukaemia (AML), abnormal self-renewal and proliferation of a cell population defined as leukaemia stem cells (LSCs) results in the accumulation of undifferentiated blast cells in the bone marrow and blood. Gene expression analyses comparing LSCs to healthy haematopoietic stem cells (HSCs) revealed a significant upregulation of the transcription factor IRX3 in the LSC compartment, and functional experiments demonstrated that IRX3 contributes to a block in differentiation. Interestingly, IRX3 is minimally expressed in HSCs and not required for normal haematopoietic development. These discoveries highlight the necessity to investigate mechanisms underlying IRX3 misexpression in AML, as well as further investigate the mechanisms through which IRX3 expression contributes to the differentiation block. To investigate the mechanism of IRX3 misexpression in AML, we applied long-range chromatin interaction analyses, genome editing, enhancer-function studies and diverse bioinformatics tools in both AML cell lines and primary patient samples. We characterise for the first time a cluster of bona-fide enhancers and its associated transcript (eRNA), and describe a model through which these regulatory elements contribute to IRX3 expression. The cluster is composed of four modules with IRX3-regulatory activity in AML cells. Moreover, transcripts arise from the E2 module and aids in the function of the super-enhancer by falicitating a chromatin loop with the IRX3 promoter and maintaining high levels of H3K27ac at both the enhancer modules and IRX3 promoter.

ORGANISM(S): Homo sapiens

PROVIDER: GSE225520 | GEO | 2025/01/21

REPOSITORIES: GEO

ACCESS DATA

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Project description:Patients with acute myeloid leukaemia (AML) often achieve remission yet subsequently die of disease relapse, which is commonly driven by chemotherapy-resistant leukaemic stem cells (LSCs). LSCs are defined by their capacity to initiate leukaemia in immuno-compromised mice. This precludes an analysis of their interaction with lymphocytes as components of anti-tumour immunity, which LSCs must escape in order to induce cancer7. Here we propose that stemness and immune evasion are closely intertwined in human AML. Using human AML xenograft and syngeneic mouse leukemia models, we show that ligands of the danger detector NKG2D, a critical mediator of anti-tumour immunity by cytotoxic lymphocytes such as natural killer (NK) cells, are generally expressed on bulk AML cells but not on LSCs. Functional LSCs can be isolated by their lack of NKG2D ligand (NKG2DL) expression, even in human AMLs not expressing the conventional LSC marker CD34. NKG2DL expressing AML cells are cleared by NK cells while NKG2DLneg leukaemic cells isolated from the same individuals escape NK cell killing. These NKG2DLneg AML cells show an immature morphology, display molecular and functional stemness characteristics, can initiate serially re-transplantable leukaemia and survive chemotherapy in patient-derived xenotransplants (PDX). Mechanistically, poly-ADP-ribose polymerase 1 (PARP1) negatively regulates NKG2DL and PARP1 inhibition (PARPi) induces NKG2DL surface expression in LSCs. Consequently, co-treatment with PARPi and NK cells suppresses leukaemogenesis in PDX models. Low expression of surface NKG2DL as well as high PARP1 expression are associated with inferior clinical outcome in patients with AML. In summary, our data link the concept of LSCs to immune escape and indicate absence of immunostimulatory NKG2DL as a novel method to identify LSCs across genetic AML subtypes. Moreover, we provide a strong rationale for targeting therapy resistant LSCs by PARP1 inhibition rendering them amenable to NK cell control in vivo.