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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151126 | GEO | 2021/11/23

REPOSITORIES: GEO

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Project description:To evaluate the long-term growth potential of BCR-ABL-transduced primitive human hematopoietic cells, lin- cord blood cells containing an MSCV-BCR-ABL-IRES-GFP (BCR-ABL) or control-GFP transgene (MIG) were injected IP into fetal goats at 45-55 days of gestation. Six transplant goats were born alive. One was examined three weeks after birth and showed GFP+ cells in the blood, bone marrow (BM), liver, kidney, lung, heart, and both skeletal and smooth muscle. FISH analysis also showed the liver of this goat contained BCR-ABL-GFP transgenic cells. The remaining five goats appear normal although, in some, the WBC count is elevated 3- to 5-fold. GFP+ cells, including cells identifiable by FACS as human CD34+ cells, have been detected in the blood of all these goats. The presence of BCR-ABL-GFP transgenic cells in the BM and liver was confirmed by FISH analysis, and quantitative real-time PCR analysis of genomic DNA isolated from unpurified BM cells obtained from three of the transplant goats demonstrated 3-5Ã104 copies of the transgene per microgram of DNA. Microarray transcript profiling was performed on blood and liver tissues of normal goats, BCR-ABL chimeric goats, MIG chimeric goats, and normal human samples. RNA for human genes was detected in goats transplanted with cord blood cells but not in normal goats, and the RNA abundance of some genes in BCR-ABL chimeric goat blood was similar to or greater than levels observed in MIG goat blood or normal human samples. Quantitative RT-PCR confirmed the differential expression of several genes in goats carrying the BCR-ABL vs. control transgene. These results demonstrate long-term engraftment but slow expansion in a large animal model of primitive human hematopoietic cells transduced with a BCR-ABL fusion gene and transplanted in utero. This novel xenotransplant goat model should be useful for analyzing the initial phases of development of human CML and for assessing new therapies with potential long-term benefits. Experiment Overall Design: Total RNA was extracted from liver (L) and blood (B) samples of normal goats (ng), humans (hu), chimeric goats engrafted with human cord blood stem cells containing control (mig) vector, and chimeric goats engrafted with CML (bcrabl) vector. RNA samples were profiled on Affymetrix human U133A GeneChips and examined for differentially expressed genes in CML vs control goats, filtering for signals significantly above background levels observed in normal goat to select for specific human gene expression.

Project description:The microarray data presented here relate to a study on TEL-AML1 associated childhood leukemia (Hong et al, 2008) the abstract of which is as follows: "Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of childhood precursor B-cell acute lymphoblastic leukemia characterised by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children which can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one pre-leukemic and one with frank leukemia, we establish the lineal relationship between these "tumor-propagating" cells and the pre-leukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1 transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this pre-leukemic cell with altered self-renewal and survival properties." The cells used to generate the microarray data were obtained as follows: We prospectively isolated CD34+CD38-/lowCD19+ cells from NOD/SCID mice transplanted with TEL-AML1-transduced human cord blood cells and compared their gene expression profiles, ascertained by affymetrix microarray analysis (see methods), to control 'hematopoietic stem cells' (HSCs immunophenotypically-defined as CD34+CD38-/lowCD19-) and pro-B cells (immunophenotypically-defined as CD34+CD38+CD19+) isolated from NOD/SCID animals transplanted with control vector transduced cord blood cells. While these different populations were obtained from three independent transduction and transplantation experiments, the data were generated from small numbers of cells and have not been validated by independent analyses such as RQ-PCR or protein analysis. They should therefore be regarded as preliminary in nature and we would therefore caution against detailed analysis of individual gene expression profiles based on these particular datasets. This caveat aside, the data may provide a broad overview of gene expression profiles in these cell types and such analyses suggest that TEL-AML1 generates a novel population of cells that contain features of both stem cells and committed B progenitors (Hong et al 2008). We are currently repeating the analyses using larger numbers of cells and more replicates together with appropriate cell populations from ALL patients and will post these data online when they become available.

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

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