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An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

ABSTRACT: An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

PROVIDER: PRJNA785656 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17106103_1.fastq.gz	Fastqsanger.gz
	SRR17106103_2.fastq.gz	Fastqsanger.gz
	SRR17106104_1.fastq.gz	Fastqsanger.gz
	SRR17106104_2.fastq.gz	Fastqsanger.gz
	SRR17106105_1.fastq.gz	Fastqsanger.gz

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An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia.

Project description:Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

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An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Project description:As part of our effort to elucidate the role of IL7RA aberrations, we transduced normal cord blood cells with lentivirus expressing IL7RA with activated mutation. Additionally in part of the experiments cells were transduced with lentivirus expressing CAS9 and guides targeting the CDKN2A gene. Here we deposit Single Nucleotide Polymorphism (SNP) array data of the leukemic samples that were developed after transplantation of the transduced cells in immunodeficient mice.

2021-12-05 | E-MTAB-11258 | biostudies-arrayexpress

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Project description:Bulk RNAseq for transplanted transduced (CRLF2-IL7RAins or BB control)CB cells

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An instructive role for IL7RA in the development of human B-cell precursor leukemia

Project description:An instructive role for IL7RA in the development of human B-cell precursor leukemia

| PRJNA634839 | ENA

Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia.

Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

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RNA-seq analysis for mRNA expression change in alpha-synclein fibril-treated cultured oligodendrocyte precursor cells

Project description:Glial cytoplasmic inclusion is the pathological hallmark of multiple system atrophy commonly observed as alpha-synulcien-positive aggregates within oligodendrocytes. We elucidated that preformed alpha-synulcien fibrils triggers multimerization and upsurge of endogenous alpha-synulcien in oligodendrocyte precursor cells which is attributable to insufficient autophagic proteolysis. To assess the functional influence of alpha-synuclein fibrils application on oligodendrocyte precursor cells, RNA-seq analysis was performed. The data revealed that alpha-synulcien fibrils interfered with numerous protein expressions associated with neuronal support and myelination.

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Interleukin-4 receptor signaling modulates neuronal network activity

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An instructive role for IL7RA in the development of human B-cell precursor leukemia

Project description:Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis Ã¢Â€Âœph-likeÃ¢Â€Â BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic cells creates a preleukemic state in transplanted NOD/LtSz-scid IL2RÃŽÂ³null mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolved to a BCP-ALL with spontaneously acquired CDKN2A deletions as commonly observed in primary human BCP-ALL. CRISPR mediated silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA resulted in robust development of BCP-ALLs in-vivo. Thus, we demonstrate for the first time that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

| EGAS00001005347 | EGA

Interleukin-4 receptor signaling modulates neuronal network activity [mouse]

2022-04-14 | GSE200569 | GEO

Human islets treated with alpha-difluoromethylornithine in combination with interferon-gamma and interleukin-beta

Project description:Proteomic data of human islets treated for 24h with alpha-difluoromethylornithine in combination with interferon-gamma and interleukin-beta; 6 biological replicates. Samples were digested with trypsin, then analyzed by LC-DIA-MS. Data was searched with FragPipe/DIA-NN.

2023-03-07 | MSV000091431 | MassIVE

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