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

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

PROVIDER: PRJNA634839 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11840676_1.fastq.gz	Fastqsanger.gz
	SRR11840676_2.fastq.gz	Fastqsanger.gz
	SRR11840677_1.fastq.gz	Fastqsanger.gz
	SRR11840677_2.fastq.gz	Fastqsanger.gz
	SRR11840678_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:An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

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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.

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

Project description:10X single cell analysis of human leukemia, pre-leukemia and normal control. The leukemia was developed in xenograft mice that was serialy transplanted with cells from primary mouse that was transplanted with normal cord blood after transduction with virues encoding hyper activated mutant IL7RA. The preleukemic cells are from the primary engrafted mouse and the control is the same cord blood that was transduced with backbone virus expressing GFP.

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

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