Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition

ABSTRACT: RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition

PROVIDER: PRJNA970289 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR24471121_1.fastq.gz	Fastqsanger.gz
	SRR24471121_2.fastq.gz	Fastqsanger.gz
	SRR24471122_1.fastq.gz	Fastqsanger.gz
	SRR24471122_2.fastq.gz	Fastqsanger.gz
	SRR24471123_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 38

Similar Datasets

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [ATAC-seq]

Project description:Disease-initiating mutations in the transcription factor RUNX1 occur as germline and somatic events that cause leukemias with particularly poor prognosis. However, the role of RUNX1 in leukemogenesis is not fully understood and effective therapies for RUNX1-mutant leukemias remain elusive. Here, we use primary patient samples and a RUNX1 knockout model in primary human hematopoietic cells to investigate how RUNX1 loss contributes to leukemic progression and to identify targetable vulnerabilities. Surprisingly, we found that RUNX1 loss decreased proliferative capacity and stem cell function. However, RUNX1-deficient cells selectively upregulated the interleukin-3 (IL-3) receptor. Exposure to IL-3, but not other JAK/STAT cytokines, rescued RUNX1 KO proliferative and competitive defects. Further, we demonstrated that RUNX1 loss repressed JAK/STAT signaling and rendered RUNX1-deficient cells sensitive to JAK inhibitors. Our study identifies a dependency of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which may enable these aggressive blood cancers to be targeted with existing agents.

2023-08-25 | GSE231950 | GEO

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [RNA-seq]

2023-08-25 | GSE231949 | GEO

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [RNA-seq]

Project description:RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [RNA-seq]

| PRJNA970294 | ENA

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [ATAC-seq]

Project description:RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition [ATAC-seq]

| PRJNA970296 | ENA

RUNX1 loss renders hematopoietic and leukemic cells dependent on interleukin-3 and sensitive to JAK inhibition

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-25 | GSE231951 | GEO

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle regulation to Drive Leukemic Transformation [HiC]

Project description:Oncogenic transcription factors such as the leukaemic fusion protein RUNX1/ETO constitute cancer-specific but highly challenging therapeutic targets, whose functions depend on pharmacologically tractable downstream pathways. Here we interrogated the transcriptional network of RUNX1/ETO in an in vitro/in vivo RNAi screen and identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO drives CCND2 expression by binding to a regulatory element upstream of the CCND2 promoter. Both knockdown of CCND2 and treatment with the CDK4/6 inhibitor palbociclib inhibited leukemic expansion patient-derived AML cells and impaired engraftment of immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO drives leukaemia by directly promoting cell cycle progression and establish inhibition of G1 CCND-CDK complexes as a promising therapeutic strategy for RUNX1/ETO-driven AML.

2019-04-12 | GSE117107 | GEO

The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle regulation to Drive Leukemic Transformation [ChIP]

2019-04-12 | GSE117105 | GEO

RUNX1 isoforms in leukemogenesis

Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

2023-05-10 | PXD030616 | Pride

Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice

Project description:Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL.

2021-06-28 | PXD026322 | Pride

Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice

2021-06-28 | PXD026438 | Pride