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FANCA deficiency promotes leukemic progression by allowing emergence of cells carrying oncogenic driver mutations

ABSTRACT: FANCA deficiency promotes leukemic progression by allowing emergence of cells carrying oncogenic driver mutations

PROVIDER: PRJNA690565 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13380212_1.fastq.gz	Fastqsanger.gz
	SRR13380212_2.fastq.gz	Fastqsanger.gz
	SRR13380213_1.fastq.gz	Fastqsanger.gz
	SRR13380213_2.fastq.gz	Fastqsanger.gz
	SRR13380214_1.fastq.gz	Fastqsanger.gz

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FANCA deficiency promotes leukemic progression by allowing emergence of cells carrying oncogenic driver mutations

Project description:Leukaemia is caused by the clonal evolution of a cell that accumulates mutations/genomic rearrangements, allowing unrestrained cell growth. However, recent identification of leukaemic mutations in the blood cells of healthy individuals revealed that additional events are required to expand the mutated clones for overt leukaemia. Here, we assessed the functional consequences of deleting the Fanconi anaemia A (Fanca) gene, which encodes a DNA damage response protein, in Spi1 transgenic mice that develop preleukaemic syndrome. Loss of FANCA increases SPI1-associated disease penetrance and favours leukaemic progression without increasing the global mutation load of leukaemic clones. However, leukaemic FANCA-deleted cells display heterozygote activating mutations in known oncogenes, such as Kit or Nras, that are identified at low frequency in WT mice with preleukaemic syndrome, indicating that FANCA loss-of-function supports the emergence of oncogene mutated leukaemic cells. We show that a unique transcriptional deregulation is associated with the leukaemic status of cells devoid of FANCA activity, including MDM4, NOTCH and Wnt/-catenin pathways. Our observations provide evidence that FANCA-deficient preleukaemic cells carrying oncogenic Kit or Ras mutations require a favourable intracellular environment to allow the emergence of leukaemic clones. The loss of FANCA may provide this mandatory cellular setup by allowing the simultaneous activation of several proliferative pathways.

2023-08-31 | GSE164411 | GEO

FANCA deficiency promotes leukaemic progression by allowing the emergence of cells carrying oncogenic driver mutations.

Project description: Not available

| S-EPMC10491493 | biostudies-literature

293FT Cell Endogenous FANCA Protein-Protein Interactions

2019-07-25 | PXD010570 | Pride

CCH-SCC-FA1 FANCA-essentiality screen

Project description:CCH-SCC-FA1 FANCA-essentiality screen

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EndoC-betaH3 Cell FANCA Protein Interactions Regulated by Glucose Stimulation

Project description:Hyperinsulinemia affects 72% of Fanconi anemia (FA) patients and an additional 25% experience lowered glucose tolerance or frank diabetes. The underlying molecular mechanisms contributing to the dysfunction of FA pancreas β cells is unknown. Therefore, we sought to identify previously unexplored roles of FA proteins in the glucose responsive human pancreas β cell line EndoC-βH3 using a mass spectrometry-based protein interaction analysis of endogenous FANCA. This study reveals glucose stimulation-dependent changes in the FANCA interaction network indicative of the DNA damage response (DDR) through interactions with other FA proteins. We identify protein interactions with FANCA related to β cell insulin secretion.

2019-07-25 | PXD010589 | Pride

Kinome-wide shRNA screen for synthetic lethality in patient-derived FANCA-deficient fibroblasts.

Project description:The purpose of this screen was to identify synthetic lethal targets in FANCA-deficient cells.

2021-05-24 | E-MTAB-9802 | biostudies-arrayexpress

Alisertib treatment in FANCA-deficient cell lines

Project description:Alisertib treatment in FANCA-deficient cell lines

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Inflammation favors the emergence of ETV6-RUNX1-positive pre-leukemic cells in a model of mesenchymal niche

Project description:ETV6-RUNX1 (E/R) fusion gene, arising in utero from t(12;21), is the most frequent alteration in childhood acute lymphoblastic leukemia (ALL). Despite this, E/R is insufficient to overt disease since it generates a clinically silent pre-leukemic clone which contributes to hematopoiesis but fail to out-compete normal hematopoietic progenitors. Conversely, pre-leukemic cells show increased susceptibility to malignant transformation following additional genetic insults. Infections/inflammation are the most accredited triggers for mutations accumulation and progression in E/R+ pre-leukemic cells. However, how E/R and inflammation interact in promoting leukemia, both directly or through other cellular components in the bone marrow (BM) niche, is still poorly understood. Here, we demonstrate that IL6/TNFα/ILβ pro-inflammatory cytokines cooperate with BM-MSC in promoting the emergence of E/R+ murine pro-B cells over their normal counterparts by differentially affecting their proliferation, survival and migration. Very interesting, E/R-expressing human CD34+IL7R+ progenitors, a candidate population for pre-leukemic initiation during development, were preserved within the inflamed niche compared to their normal counterparts. Finally, the extent of DNA damage and activation-induced cytidine deaminase (AID) expression increase within the inflamed niche in both cell type, potentially leading to transformation in the apoptosis-resistant pre-leukemic clone. Overall, our data provide new mechanistic insights in childhood ALL pathogenesis.

2020-02-29 | GSE134437 | GEO

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Project description:Acute Myeloid Leukemia (AML) is caused by different mutations which affect growth and differentiation of myeloid cells. Depending on the mutation sub-type, cells adopt different gene regulatory networks maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent cells (leukemic stem cells or LSCs) which escape chemotherapy and can emerge from quiescence to trigger a relapse. The signalling processes that allow such cells to re-grow remain unknown. Here, we examined the well characterised t(8;21) AML sub-type as model to address this question. We show that t(8;21) LSCs aberrantly activate the ectopic VEGF and IL-5 signalling pathways. We uncovered a regulatory circuit consisting of the driver oncoprotein RUNX1-ETO and the AP-1 / GATA2 transcription factor axis allowing LSCs to re-enter the cell cycle.

2024-01-06 | GSE226600 | GEO

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