Evolution of human BCR-ABL1 leukemia-initiating cells
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PROVIDER: PRJNA227485 | ENA |
REPOSITORIES: ENA
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Project description:Activation-Induced Cytidine Deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center B lymphocytes. Occasionally, AID targets non-Ig genes, thereby contributing to B cell lymphomagenesis. We recently reported aberrant expression of AID in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1-transduced AID-/- bone marrow had prolonged survival as compared to mice transplanted with leukemia cells generated from AID+/+ bone marrow. Consistent with a causative role of AID in genetic instability, AID-/- leukemia had a decreased frequency of amplifications, deletions and a lower frequency of mutations in non-Ig genes including Pax5 and Rhoh as compared to AID+/+ leukemias. AID-/- and AID+/+ ALL cells showed a markedly distinct gene expression pattern as determined by principle component analysis, with 2,365 genes differentially expressed. In contrast to AID+/+ leukemia, AID-/- ALL cells failed to downregulate a number of tumor suppressor genes such as Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability, aberrant somatic hypermutation, and by transcriptional inactivation of tumor suppressor genes.
2009-06-24 | GSE16751 | GEO
Project description:This comparative genomic hybridization (CGH) study investigated the effect of BCL6 on clonal evolution in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). The frequencies of copy number alterations in BCR-ABL1-transformed BCL6+/+ and BCL6-/- leukemias were determined.
2010-09-29 | GSE24400 | GEO
Project description:This comparative genomic hybridization (CGH) study investigated the effect of BCL6 on clonal evolution in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). The frequencies of copy number alterations in BCR-ABL1-transformed BCL6+/+ and BCL6-/- leukemias were determined. Three BCR-ABL1-transformed BCL6+/+ and BCL6-/- ALL samples derived from mice were maintained for 4 month in cell culture and were subjected to CGH analysis. As control samples, normal untransformed splenoytes were used.
2010-09-29 | E-GEOD-24400 | biostudies-arrayexpress
Project description:Activation-Induced Cytidine Deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center B lymphocytes. Occasionally, AID targets non-Ig genes, thereby contributing to B cell lymphomagenesis. We recently reported aberrant expression of AID in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1-transduced AID-/- bone marrow had prolonged survival as compared to mice transplanted with leukemia cells generated from AID+/+ bone marrow. Consistent with a causative role of AID in genetic instability, AID-/- leukemia had a decreased frequency of amplifications, deletions and a lower frequency of mutations in non-Ig genes including Pax5 and Rhoh as compared to AID+/+ leukemias. AID-/- and AID+/+ ALL cells showed a markedly distinct gene expression pattern as determined by principle component analysis, with 2,365 genes differentially expressed. In contrast to AID+/+ leukemia, AID-/- ALL cells failed to downregulate a number of tumor suppressor genes such as Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability, aberrant somatic hypermutation, and by transcriptional inactivation of tumor suppressor genes. Experiment Overall Design: We used microarrays to detect differences in gene expression profiles between AID expressing leukemia and AID deficient leukemia
2009-07-05 | E-GEOD-16751 | biostudies-arrayexpress
Project description:We examine the oncogenic function of the Far Upstream Element Binding Protein 1 (FUBP1) in leukemia-initiating cells. For this perpose we performed knockdown of Fubp1 in CML cells in our mouse model. Here, we transduce donor bone marrow cell with the oncogene BCR-ABL1 and Fubp1 or scrambled shRNA and transplanted in recipient mice. Lineage- BCR-ABL1+ shRNA+ cells were then sorted from diseased mice and analyzed by RNA sequencing. We compare the gene expression of the Fubp1 shRNA expressing CML cells versus the control (scrambled shRNA expressing) cells in order to identify the relevant Fubp1 target genes.
2018-12-23 | GSE124304 | GEO
Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.
2017-06-06 | GSE99656 | GEO
Project description:Activation-induced cytidine deaminase (AID) specific amplifications and deletions in BCR-ABL1 positive Leukemia mouse cells. Bone marrow from Balb/CJ WT and Balb/CJ AID KO mice was transduced with BCR-ABL1. The AID specific amplifications and deletions where analyzed with an Agilent 244A mouse whole Genome CGH Array.
2009-08-15 | GSE15093 | GEO
Project description:BCR::ABL1 drives chronic myeloid leukemia (CML) pathology and treatment, as revealed by the success of tyrosine kinase inhibitor (TKI) therapy. However, additional poorly characterized molecular mechanisms, acting independently of BCR::ABL1, play crucial roles in CML, contributing to leukemic stem cells (LSCs) persistence, drug resistance and disease progression. Here, by combining high sensitive mass spectrometry (MS)-based phosphoproteomics with the SignalingProfiler pipeline, we obtained two signaling maps reporting the BCR::ABL1 dependent and independent pro-survival signalling mechanisms, respectively. Crucial oncogenic pathways were deregulated in resistant cells. To unbiasedly discover therapeutic vulnerabilities, we implemented the Druggability Score, a computational algorithm ranking proteins according to their inferred ability to kill resistant cells when suppressed. By this strategy, we identified a novel and unexpected role for FLT3 in BCR::ABL1 independent resistance. Remarkably, pharmacological suppression of FLT3 triggers death of both resistant cell lines and patients-derived LSCs. Finally, we propose midostaurin treatment as a therapeutic option to improve the clinical outcome of non responder patients and eradicate LSCs.
2025-05-07 | PXD056957 | Pride
Project description:The Philadelphia chromosome (Ph) encoding the oncogenic BCR-ABL1 kinase defines a subset of ALL with a particularly unfavorable prognosis. Acute lymphoblastic leukemia (ALL) cells are derived from B cell precursors in most cases and typically carry rearranged immunglobulin heavy chain (IGH) variable (V) region genes devoid of somatic mutations. Somatic hypermutation is restricted to mature germinal center B cells and depends on activation-induced cytidine deaminase (AID). Studying AID expression in 108 cases of ALL, we detected AID mRNA in 24 of 28 Ph-positive ALLs as compared to 6 of 80 Ph-negative ALLs. Forced expression of BCR-ABL1 in Ph-negative ALL cells and inhibition of the BCR-ABL1-kinase showed that aberrant expression of AID depends on BCR-ABL1 kinase activity. Consistent with aberrant AID expression in Ph-positive ALL, IGH V region genes and BCL6 were mutated in many Ph-positive but unmutated in most Ph-negative cases. In addition, AID introduced DNA-single-strand breaks within the tumor suppressor gene CDKN2B in Ph-positive ALL cells, which was sensitive to BCR-ABL1 kinase inhibition and silencing of AID expression by RNA interference. These findings identify AID as a BCR-ABL1-induced mutator in Ph-positive ALL cells, which may be relevant with respect to the particularly unfavorable prognosis of this leukemia subset. Keywords: gene expression array-based (RNA / in situ oligonucleotide)
2007-04-03 | GSE7182 | GEO
Project description:Coordinated BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. Persistence of oncogenic p27 functions despite effective inhibition of BCR-ABL1 may contribute to resistance to tyrosine kinase inhibitors. BCR-ABL1 induced p27 versus knockout, controlling with Empty vector p27 versus knock out
2014-10-08 | E-GEOD-59168 | biostudies-arrayexpress