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IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program II

ABSTRACT: IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program II

PROVIDER: PRJNA493794 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7939970_1.fastq.gz	Fastqsanger.gz
	SRR7939970_2.fastq.gz	Fastqsanger.gz
	SRR7939971_1.fastq.gz	Fastqsanger.gz
	SRR7939971_2.fastq.gz	Fastqsanger.gz
	SRR7939972_1.fastq.gz	Fastqsanger.gz

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IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program I

Project description:We report that IKZF2 is required for maintaining chromatin accessibility in leukemic stem cells in myeloid leukemia. RNA seq and ATAC-seq were performed to investigate the changes in chromatin accessibility of differentially expressed genes in leukemic stem cells when IKZF2 was absent. We found that IKZF2 maintains open accessibility in self-renewal transcription factor motifs such as HOXA9 sites whereas motifs of differentiation transcription factors including C/EBPs are kept closed.

2017-12-21 | GSE108367 | GEO

IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program II

2018-09-29 | GSE120623 | GEO

IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program

Project description:IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program

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IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program I

Project description:IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program I

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Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells

Project description:Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1 alpha (CK1α) termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cell lines through CK1α–p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or the analog DEG-77 delays leukemia progression in murine and human AML mice models. Overall, we provide a strategy for multi-targeted degradation of IKZF2/CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.

2023-03-08 | PXD039474 | Pride

IKZF2 is required for myeloid leukemic stem cells by driving self-renewal and inhibiting the myeloid differentiation program

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

2018-09-29 | GSE120630 | GEO

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Project description:Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.

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Pre-leukemic Cebpa mutant myeloid progenitors

Project description:In this study, we use pre-malignant cells from different Cebpa mutant acute myeloid leukemia (AML) models. We have used conditional KO models (CreLoxP) and isolated hematopoietic cells shortly after induction of recombination, in order to look at pre-leukemic cells, which have acquired the first hit, but not yet undergone full malignant transformation. We have sorted granulocyte-macrophage progenitors (GMPs) and the more immature population pre-granulocyte-macrophages (preGMs) from pre-leukemic mice. We analyzed gene-expression profiles in order to find deregulated genes, which make the cells more prone to undergo transformation.

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ChIP-seq HELIOS (Ikzf2)

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Design and development of IKZF2 and CK1α dual degraders

Project description:Lenalidomide achieves its therapeutic efficacy by recruiting and removing proteins of therapeutic interest through the E3 ligase substrate adapter cereblon. Here, we report the rational design and characterization of 81 cereblon ligands for their ability to degrade the transcription factor Helios (IKZF2) and casein kinase 1 alpha (CK1α) in acute myeloid leukemia MOLM-13 cells. Using a structure-based approach, we identified a key naphthamide scaffold that depleted both intended targets. Structure-activity relationship studies for degradation of the desired targets over other targets (IKZF1, GSPT1) afforded an initial lead compound, termed DEG-35. A subsequent scaffold replacement campaign informed by degradation profiles against a panel of substrates identified DEG-77, which selectively degrades IKZF2 and CK1α, and possesses suitable pharmacokinetic properties, solubility, and selectivity for in vivo studies. Finally, we show that DEG-77 has antiproliferative activity in diffuse large B cell lymphoma (DLBCL) cell line OCI-LY3 and ovarian cancer cell line A2780, indicating that these dual degraders and their targets may have efficacy against additional cancer types.

2024-01-04 | PXD045327 | Pride

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