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Imatinib induces mesenchymal stem cell-mediated drug resistance in BCR-ABL–positive acute lymphoblastic leukemia

ABSTRACT: One of the main objective of this study is to characterize Imatinib induced MSCs-mediated resistance evolution in BCR-ABL+ ALL. Tyrosine kinase inhibitor (TKI) Imatinib (IM) is used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to IM therapy develops rapidly in a substantial proportion of treated patients, and the molecular mechanisms underlying the resistance are poorly understood. In this study, we identified a novel cascade of consequential events that are initiated by IM, which traverse through mesenchymal stem/stromal cells (MSCs) to leukemic cells, and lead to IM resistance. Our data showed that MSCs exposed to IM were decreased in their stemness and acquired a new functional status that enabled the formation of leukemic cell niches. These MSCs had increased expression of genes encoding chemo-attractants, adhesion molecules, and pro-survival stimulant growth factors. We found that BCR-ABL+ leukemic cells persistently exposed to IM were able to switch from BCR-ABL–driven signaling to growth factor–driven signaling for survival, and this switch was reversible. Blocking both the BCR-ABL–driven pathway and the growth factor–driven JAK pathway effectively eradicated the leukemic cell niches. Our findings illustrate TKI-induced, MSC-mediated drug resistance, suggesting an effective way to eliminate this type of drug resistance in patients with BCR-ABL+ ALL.

ORGANISM(S): Mus musculus

PROVIDER: GSE56472 | GEO | 2015/09/01

SECONDARY ACCESSION(S): PRJNA243379

REPOSITORIES: GEO

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Imatinib induces mesenchymal stem cell-mediated drug resistance in BCR-ABL–positive acute lymphoblastic leukemia

Project description:One of the main objective of this study is to characterize Imatinib induced MSCs-mediated resistance evolution in BCR-ABL+ ALL. Tyrosine kinase inhibitor (TKI) Imatinib (IM) is used as a frontline therapy for BCR-ABL–positive (BCR-ABL+) acute lymphoblastic leukemia (ALL). However, resistance to IM therapy develops rapidly in a substantial proportion of treated patients, and the molecular mechanisms underlying the resistance are poorly understood. In this study, we identified a novel cascade of consequential events that are initiated by IM, which traverse through mesenchymal stem/stromal cells (MSCs) to leukemic cells, and lead to IM resistance. Our data showed that MSCs exposed to IM were decreased in their stemness and acquired a new functional status that enabled the formation of leukemic cell niches. These MSCs had increased expression of genes encoding chemo-attractants, adhesion molecules, and pro-survival stimulant growth factors. We found that BCR-ABL+ leukemic cells persistently exposed to IM were able to switch from BCR-ABL–driven signaling to growth factor–driven signaling for survival, and this switch was reversible. Blocking both the BCR-ABL–driven pathway and the growth factor–driven JAK pathway effectively eradicated the leukemic cell niches. Our findings illustrate TKI-induced, MSC-mediated drug resistance, suggesting an effective way to eliminate this type of drug resistance in patients with BCR-ABL+ ALL. Gene expression signatures were compared from triplicate samples of MSCs that were either treated with vehicle or imatinib for 32, 64 and 96 hours.

2015-09-01 | E-GEOD-56472 | biostudies-arrayexpress

iTRAQ analysis of K562 cell line

Project description:K562 cells untreated (S) and treated (S+IM) with Imatinib as well as sensitive (S+IM) and resistant (R) to imatinib were subjected to labelled quantification by iTRAQ to identify Bcr-Abl downstream signaling components and proteins modulated in resistance respectively

2021-10-05 | PXD025173 | Pride

Exosomes released by imatinib-resistant K562 cells carry specific membrane markers and increase survival of imatinib-sensitive cells in the presence of imatinib.

Project description:Chronic myeloid leukemia is a malignant hematopoietic disorder distinguished by a presence of BCR-ABL fused oncogene with constitutive kinase activity. Although targeted therapy by tyrosine kinase inhibitors (TKI) markedly improved patient´s survival and quality of life, development of drug resistance remains a critical issue for a subset of patients. The most common mechanism of TKI resistance in CML patients is a mutation in BCR-ABL gene which makes oncogenic Bcr-Abl protein insensitive to TKI therapy. Mutation independent mechanisms of TKI resistance are less elucidated, but exosomes, extracellular vesicles excreted from normal and tumor cells were recently linked with cancer progression and drug resistance. We used an imatinib-sensitive CML cell line K562 and derived an imatinib-resistant subline K562IR by prolonged cultivation of cells in presence of imatinib. We demonstrated that exosomes isolated from K562IR cells are internalized by K562 cells and increase their survival in presence of 2µM imatinib. To characterize the exosomal cargo and to identify resistance-associated marker proteins, we performed a deep proteomic analysis of exosomes from both cell sublines using label free quantification (LFQ). In total, we identified over 3000 exosomal proteins including 31 proteins differentially abundant in exosomes derived from K562IR cells. Among the differential proteins were three massively upregulated membrane proteins in K562IR exosomes with surface localization: IFITM3, CD146, CD36. We verified the massive upregulation of the three proteins in K562IR exosomes and also in K562IR cells. Using flow cytometry, we further demonstrated potential of CD146 as cell surface marker associated with imatinib resistance in K562 cells.

2024-10-24 | PXD019283 | Pride

Identification of a novel lncRNA family that is required for efficient cellular transformation by Bcr-Abl oncogene

Project description:Aberrantly expressed long noncoding RNAs (lncRNAs) have been described in diverse human diseases and cancer development. Chronic myeloid leukemia (CML) is a hematological malignancy induced by Bcr-Abl hybrid gene. Owing to the development of tyrosine kinase inhibitors (TKIs), especially the first-generation Imatinib, over 90% of CML patients can be cured in recent years. Here we attempt to identify Imatinib-inducible lncRNAs associated with CML by analyzing lncRNA expression profiles in K562 cells after Imatinib or control treatment. LncRNA microarray analysis revealed that numerous lncRNAs were differentially expressed in K562 cells after Imatinib treatment. In this study, we focus on a conserved, Imatinib-inducible lncRNA (IIR) family, named lncRNA-IIRX. Upregulation of lncRNA-IIRX has been detected in both human and mouse Abl-transformed cell lines after Imatinib treatment. Interestingly, lncRNA-IIRX levels were significantly lower in leukemic cells derived from Bcr-Abl-positive ALL patients than those in normal control group. Furthermore, altering lncRNA-IIRX expression remarkably affected survival of Abl-transformed leukemic cells, and tumorigensis induced by these leukemic cells in xenograft mouse model. Knockdown of lncRNA-IIRX in transgenic mice significantly promoted Bcr-Abl-mediated primary bone marrow transformation, and leukemia development in leukemia mouse model. These results indicate that lncRNA-IIRX functions as a suppressor gene in Bcr-Abl-induced tumorigenesis, and may provide novel insights into complicated mechanisms underlying cellular transformation by Bcr-Abl oncogene. This microarray was performed to identify Imatinib-inducible lncRNAs associated with CML.

2019-04-17 | GSE119770 | GEO

Imatinib therapy of chronic myeloid leukemia restores the expression levels of key genes for DNA damage and cell cycle progression

Project description:Background: Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. It is well known that CML cells are genetically unstable. However, the mechanisms by which these cells acquire genetic alterations are poorly understood. Imatinib mesylate (IM) is the standard therapy for newly diagnosed CML patients. IM targets the oncogenic kinase activity of BCR-ABL. Objective: To study the gene expression profile of BM hematopoietic cells in the same patients with CML before and one month after imatinib therapy. Methods: Samples from patients with CML were analyzed using Affymetrix GeneChip Expression Arrays. Results: A total of 594 differentially expressed genes, most of which (393 genes) were downregulated, as a result of imatinib therapy were observed. Conclusions: The blockade of oncoprotein Bcr-abl by imatinib could cause a decrease in the expression of key DNA repair genes, and cells try to restore the normal gene expression levels required for cell proliferation and chromosomal integrity.

2014-01-01 | GSE33075 | GEO

Comparative analysis of BCR-ABL tyrosine kinase inhibitors in BCR-ABL positive K562 cells

Project description:Tyrosine kinase activity is the crucial enzymatic activity driving all known functions of the BCR-ABL protein and is required for protection from apoptosis by BCR-ABL, therefore, targeting this enzyme is an effective approach for therapeutic strategies. Recently, a novel structural entity, imatinib (STI571; Novartis, Basel, Switzerland), a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL, has shown promise against Ph-positive leukemia in human clinical trials. However, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for overriding chemotherapy to eradicate this disease. AMN107 and BMS-354825 are clinically active “next-generation” BCR-ABL inhibitors. One potentially powerful approach is to use these compounds in combination with imatinib. The rationale for such approaches is that an inhibitor cocktail may target the widest range of resistant clones and thereby delay the onset of acquired drug resistance. More potent BCR-ABL inhibitors would be to target residual leukemia that persists in patients in whom imatinib induces durable remission but failed to eradicate the disease. From these points, our studies are performed to determine (1) the differences of molecular signaling pathways between BMS-354825 and imatinib (2) the mechanisms by which drug resistance of BMS-354825 and imatinib occur except for point mutation of BCR-ABL kinase domain. Keywords: drug sensitivity

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BCR-ABL triggers a glucose-dependent survival program during leukemogenesis through the suppression of TXNIP

Project description:Imatinib is highly effective in the treatment of chronic myelogenous leukemia (CML), but the primary and acquired imatinib resistance remains the big hurdle. Molecular mechanisms for CML resistance to tyrosine kinase inhibitors, beyond point mutations in BCR-ABL kinase domain, still need to be addressed. Here, we demonstrated that TXNIP is a novel BCR-ABL target gene. Suppression of TXNIP is responsible for BCR-ABL triggered glucose metabolic reprogramming and mitochondrial homeostasis. Mechanistically, Miz-1/P300 complex transactivates TXNIP through the recognition of TXNIP core promoter region, responding to the c-Myc suppression by either imatinib or BCR-ABL knockdown. TXNIP restoration sensitizes CML cells to imatinib treatment and compromises imatinib resistant CML cell survival, predominantly through the blockage of both glycolysis and glucose oxidation which results in the mitochondrial dysfunction and ATP production. In particular, TXNIP suppresses expressions of the key glycolytic enzyme, HK2 and LDHA, potentially through Fbw7-dependent c-Myc degradation. In accordance, BCR-ABL suppression of TXNIP provides a novel survival pathway for the transformation of mouse BM cells. Combination of drug inducing TXNIP expression with imatinib synergistically kills CML cells from patients and further extends the survival of CML mice. Thus, the activation of TXNIP represents an effective strategy for CML treatment to overcome resistance.

2023-05-03 | GSE218451 | GEO

Charaterization of genetic alterations and gene expression signatures found in BCR-ABL inhibitor-resistant KCL-22 subpopulations and single clones

Project description:KCL-22 is a chronic myeloid leukemia (CML) cell line derived from a patient in blast crisis phase and harbors the BCR-ABL translocation. The catalytic (ATP-competitive) BCR-ABL inhibitors imatinib and nilotinib have dramatically improved CML patient outcome, but the development of resistance remains a clinical challenge. The recent identification of allosteric BCR-ABL inhibitors, such as GNF-2, which target the enzyme by binding to the myristoyl pocket rather than catalytic site of ABL1, may provide a strategy to broadly overcome resistance to the class of ABL1 ATP competitive inhibitors. We therefore wanted to use the ClonTracer barcoding system to compare the clonal responses of KCL-22 to imatinib, nilotinib and GNF-2. RNA-seq was employed to characterize genetic alterations and gene expression signatures in the pooled cell populations resistant to BCR-ABL inhibitors as well as single clones showing differential response to the three inhibitors. mRNA profiling of the subpopulations and single clones of human CML cell line KCL-22 that contribute to BCR-ABL inhibitor resistance

2014-10-07 | E-GEOD-62121 | biostudies-arrayexpress

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2011-03-01 | E-GEOD-24381 | biostudies-arrayexpress

Chronic myelogenous leukemia hematopoietic stem cells

Project description:We show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin- CD34-) hematopoietic stem cells (HSCs) from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular caryotyping and quantitative analysis of BCR/ABL transcript demonstrated that about one third of CD34- was leukemic. CML CD34- cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures and cytokines induced CD34 expression on some HSCs, cell cycling, acquisition of clonogenic activity and increased expression of BCR/ABL transcript. CML CD34- cells showed an engraftment rate in immunodeficient mice similar to that of CD34+ cells. Gene expression profiling revealed the down-regulation of cell cycle arrest genes together with genes involved in antigen presentation and processing, while the expression of angiogenic factors was strongly up-regulated when compared to normal counterparts. Flow cytometry analysis confirmed the significant down-regulation of HLA class I and II molecules in CML CD34-cells. Increasing doses of imatinib mesilate (IM) did not affect fusion transcript levels, BCR-ABL kinase activity and the clonogenic efficiency of CML CD34- cells as compared to leukemic CD34+cells. Thus, we identified in CML a novel CD34- leukemic stem cell subset with peculiar molecular and functional characteristics which may be a potential target for CML therapeutics.

2010-01-05 | GSE11675 | GEO

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