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Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [RNA-seq CTV]

ABSTRACT: The leukemic stem cell concept is well established in B-acute lymphoblastic leukemia (B-ALL). However, the question of how a primary oncogene reprograms stem cell-like properties in committed B-cells and leads to a pre-neoplastic population remains unclear. Here, we used the PAX5-ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal and the emergence of pre-leukemic stem cells (pre-LSCs). Through multi-parametric immunophenotyping, we show that PAX5-ELN oncoprotein disrupts the differentiation of pre-leukemic cells by enforcing the IL7r/JAK-STAT signaling pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B-cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Collectively, our study sheds new lights on the biological mechanisms underlying the cell-of-origin of leukemia. We performed gene expression profiling analysis using data obtained from RNA-seq of quiescent, slowly prolfierative or highly proliferative B-cells coming from WT or PEtg mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE210924 | GEO | 2023/11/01

REPOSITORIES: GEO

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Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [ATAC-seq]

Project description:The leukemic stem cell concept is well established in B-acute lymphoblastic leukemia (B-ALL). However, the question of how a primary oncogene reprograms stem cell-like properties in committed B-cells and leads to a pre-neoplastic population remains unclear. Here, we used the PAX5-ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal and the emergence of pre-leukemic stem cells (pre-LSCs). Through multi-parametric immunophenotyping, we show that PAX5-ELN oncoprotein disrupts the differentiation of pre-leukemic cells by enforcing the IL7r/JAK-STAT signaling pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B-cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Collectively, our study sheds new lights on the biological mechanisms underlying the cell-of-origin of leukemia.

2023-11-01 | GSE210923 | GEO

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [H2Bgfp]

2023-11-01 | GSE210925 | GEO

Cell-Cycle Restriction Sustains Therapy-Resistant Pre-Leukemic Stem Cells

Project description:Pre-leukemic stem cells (pre-LSCs) provide a reservoir of cells that evolve to acute leukemia and cause relapse following chemotherapy. We postulated that quiescence of pre-LSCs is an important mechanism of therapeutic resistance. Using a doxycycline-inducible H2B-GFP transgene in a mouse model of T-cell acute lymphoblastic leukemia, we show that long-term self-renewal, clonal evolution and resistance to chemo-radiation are intrinsically linked to restricted cell cycle. We show that restricted cell cycle of pre-LSCs requires the presence of the CDK inhibitor p21, with absence of p21 leading to chemosensitivity and clonal extinction by loss of asymmetric cell division and terminal differentiation. These results provide a model to identify and test strategies to eradicate an important source of clonal evolution and leukemic relapse.

2018-12-21 | GSE110132 | GEO

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 40 samples comprising sevenfold replicates of transductions with empty vector, wild type PAX5 and 4 mutant PAX5 constructs

2013-08-01 | E-GEOD-45260 | biostudies-arrayexpress

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

2013-08-01 | GSE45260 | GEO

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

2014-04-06 | GSE45834 | GEO

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress

Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

Project description:A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from both families exhibited 9p deletion, with loss-of-heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 10 samples of J558 murine myeloma cells infected with MSCV-Puro-IRES-GFP (PIG) empty vector (EV; three independent replicates), MSCV-PIG Pax5 WT (WT; three independent replicates), and MSCV-PIG Pax5 G183S (Mut; four independent replicates). Cells were selected with puromycin after infection for 5-7 days, subsequently cells were sorted for GFP and IgM expression by FACS.

2014-04-06 | E-GEOD-45834 | biostudies-arrayexpress

Genome-wide comparison of gene expression level between leukemia stem cells in different tissues

Project description:Analysis of gene expression of leukemia stem cells (LSCs) in different tissues. The hypothesis is that the distinct niche in different tissues affects the gene expression of LSCs. Total RNA from LSCs in different tissues including bone marrow (BM), spleen (SPL), peripheral blood (BL), gonadal adipose tissue (AT) as well as normal counterparts for LSCs from normal BM (NBM) was isolated and subjected to RNA-seq. LSCs were derived from a blast crisis chronic myeloid leukemia (bcCML) murine model induced by co-expression of human leukemic oncogenes BCR-ABL and NUP98-HOXA9. Triplicates were generated for LSCs from each tissues.

2016-07-07 | E-GEOD-81842 | biostudies-arrayexpress

Proteomics analysis for RBM17 in acute myeloid leukemia

Project description:Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. We performed shotgun proteomics to characterize the proteome changes upon RBM17 knockdown in AMl cells. In addition, we used proteomics to analyze the proteome changes after knockdown of EIF4A2, a direct splicing substrate of RBM17 in AML cells.

2022-08-12 | PXD026780 | Pride

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