Heterogeneity of therapy-resistant CML cells
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ABSTRACT:
PROVIDER: PRJNA850635 | ENA |
REPOSITORIES: ENA
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Project description:Heterogeneity of CML therapy resistant cells
| PRJNA885102 | ENA
Project description:Purpose: We previously demonstrated that immunophenotypically CD34-CD38- TKI resistant LSC/LIC population was clearly heterogeneous. The goal of this study is to explore more about the drug-resistant LSC/LICs Methods: CML patient cells were treated for 7 days with imatinib and live cells were subjected to scRNA-sequencing Results: scRNA-seq reveals heterogeneity in the therapy resistant cells. Distinct expression profiles, yet with an interrelated continuumsuggest the existence of a depply-quiescent persister population within resistant cells. Conclusions: In this study using single cell transcriptomics and single cell metabolomics analyses we identify and characterize a deeply-quiescent/persister CML LSC/LIC population subset of CML patient cells which is highly dependent on FAO for their metabolomic requierements
2023-06-16 | GSE206421 | GEO
Project description:A deeper understanding of the biology of therapy resistant cells is important for the development of optimal therapeutic strategies to attain complete cure of leukemia. Here we compared chromatin accessibility of CML patient cells treated with Imatinib vs untreated cells and column enriched deep-quiescent LI (leukemia initiator) cells. ICG-001 treatment of LIs suggested increased differentiation of LIs.
2023-03-30 | GSE214385 | GEO
Project description:Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC-population in chronic phase (CP) chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CP-CML and demonstrate differences in response to subsequent TKI-treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI-therapy compared to subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CP-CML stem cell markers CD25, CD26 and IL1RAP is high on all subpopulation at diagnosis, but downregulated and unevenly distributed across subpopulations in response to TKI-treatment. The most TKI-insensitive cells of the LSC-compartment can be captured within the CD45RA- fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Thus, our results reveal the heterogeneity of the CML stem cell population and propose a Lin-CD34+CD38-/lowCD45RA-cKIT-CD26+ population to be targeted for improved therapy response.
2017-01-27 | GSE84507 | GEO
Project description:In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model . Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.
2024-05-30 | GSE262421 | GEO
Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound â¥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells. Experiment Overall Design: In total 6 patients with new diagnosis CML (Chronic Myelogenous Leukemia) in chronic phase are inculded in the study. The gene expression profiles of the CD34+ hematopoietic stem and progenitor cells from the patients before first treatment with Glivec (Imatinib) are compared to the gene expression profiles of the CD34+ hematopoietic stem and progenitor cells of the same patients after 7 days of treatment with 400 mg Glivec / day.
2008-10-21 | E-GEOD-12211 | biostudies-arrayexpress
Project description:Imatinib has become the current standard therapy for patients with chronic myelogenous leukaemia (CML). For a better understanding of the Imatinib-related molecular effects in vivo, we assessed gene expression profiles of Philadelphia Chromosome positive (Ph+) CD34+ cells from peripheral blood of 6 patients with de novo CML in chronic phase. After 7 days of treatment with Imatinib the Ph+ CD34+ cells were reassessed to look for changes in the transcriptome. The expression level of 303 genes was significantly different comparing the transcriptome of the Ph+ CD34+ cells before and after 7 days of Imatinib therapy (183 down-regulated, 120 up-regulated, lower bound ≥1.2-fold). For a substantial number of genes governing cell cycle and DNA replication, the level of expression significantly decreased (CDC2, RRM2, PCNA, MCM4). On the other hand, therapy with Imatinib was associated with an increase of genes related to adhesive interactions, such as L-selectin or CD44. A group of 8 genes with differential expression levels were confirmed using a gene specific quantitative real-time PCR. Thus, during the first week of treatment, Imatinib is preferentially counteracting the bcr-abl induced effects related to a disturbed cell cycle and defective adhesion of leukemic Ph+ CD34+ cells.
2008-07-30 | GSE12211 | GEO
Project description:Properties of cancer stem cells (CSC) involved in drug-resistance and relapse have significant effect on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myelogenous leukemia (CML), TKIs have not fully cure CML due to TKI-resistant CML stem cells. Moreover, the relapse after discontinuation of TKIs has not been predicted in CML patients with best TKI-response. In our study, pre-hematoopoietic progenitor cells (pre-HPCs), a model of CML stem cells derived from CML-iPSCs identified a novel antigen of TKI-resistant CML cells. Even in the fraction reported as TKI-sensitive, the antigen+ cells showed TKI-resistance in CML patients. In addition, residual CML cells in patients with optimal TKI-response were concentrated in the antigen+ population.
2016-12-21 | GSE92624 | GEO
Project description:Tyrosine kinase inhibitors (TKIs) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia initiating cells (LICs) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs, required for colony formation, and survival and cell cycle progression of CML cell lines. A critical role for Ezh2 is supported by genetic studies in a mouse CML model. Inactivation of Ezh2 in conventional conditional mice and through CRISPR/Cas9-mediated gene editing prevents initiation and maintenance of disease and survival of LICs, irrespective of BCR/ABL1 mutational status, and extends survival. Expression of the Ezh2 homolog Ezh1 is reduced in Ezh2-deficient CML LICs, creating a scenario resembling complete loss of PRC2. EZH2-dependence of CML LICs raises prospects for improved therapy of TKI-resistant CML and/or eradication of disease by addition of EZH2 inhibitors.
2016-08-18 | GSE85744 | GEO
Project description:The advent of tyrosine kinase inhibitors (TKIs) as treatment of Chronic Myeloid Leukemia (CML) is a paradigm in molecularly targeted cancer therapy. Nonetheless, TKI insensitive leukemia stem cells (LSCs) persist in most patients, even after years of treatment. Here, we used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to generate high-resolution single cell multiomics maps from CML patients stratified according to molecular response (BCR-ABL IS %) following 12 months of TKI therapy. Simultaneous measurement of global gene expression profiles together with >40 surface markers from the same cells revealed that each patient harbored a unique composition of stem and progenitor cells at diagnosis demonstrating that cellular heterogeneity is a hallmark of CML. The patients with treatment failure at 12 months of therapy had markedly higher abundance of molecularly defined primitive cells at diagnosis compared to the optimal responders. The multi-modal feature landscape enabled visualization of the primitive fraction as a mix of Lin-CD34+38-/low BCR-ABL1+ LSCs and BCR-ABL1- HSCs in variable ratio across patients and guided their prospective isolation by a combination of CD26 and CD35 cell surface markers.
2024-01-17 | GSE236233 | GEO