Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Xu Y
PROVIDER: S-EPMC5834470 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Chronic myelogenous leukemia (CML) results from transformation of a long-term hematopoietic stem cell (LTHSC) by expression of the BCR-ABL fusion gene. However, BCR-ABL-expressing LTHSCs are heterogeneous in their capacity as leukemic stem cells (LSCs). Although discrepancies in proliferative, self-renewal, and differentiation properties of normal LTHSCs are being increasingly recognized, the mechanisms underlying heterogeneity of leukemic LTHSCs are poorly understood. Using a CML mouse model, we identified gene expression differences between leukemic and nonleukemic LTHSCs. Expression of the thrombopoietin (THPO) receptor MPL was elevated in leukemic LTHSC populations. Compared with LTHSCs with low MPL expression, LTHSCs with high MPL expression showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro and increased leukemogenic capacity in vivo. Although both G0 and S phase subpopulations were increased in LTHSCs with high MPL expression, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSCs reduced THPO-induced JAK/STAT signaling and leukemogenic potential. These same phenotypes were also present in LTHSCs from patients with CML, and patient LTHSCs with high MPL expression had reduced sensitivity to BCR-ABL tyrosine kinase inhibitor treatment but increased sensitivity to JAK inhibitors. Together, our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSCs and suggest that high MPL-expressing CML stem cells are potential targets for therapy.
| S-EPMC4767357 | biostudies-literature
Project description:Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) 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 and 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.SignificanceThis work defines EZH2 as a selective vulnerability for CML cells and their LICs, regardless of BCR-ABL1 mutational status. Our findings provide an experimental rationale for improving disease eradication through judicious use of EZH2 inhibitors within the context of standard-of-care TKI therapy. Cancer Discov; 6(11); 1237-47. ©2016 AACR.See related article by Scott et al., p. 1248This article is highlighted in the In This Issue feature, p. 1197.
| S-EPMC5096974 | biostudies-literature
Project description:Noncoding RNAs are increasingly being accredited with key roles in gene regulation during development and disease. Here we report the discovery and characterization of a novel long noncoding RNA, Hmrhl, which shares synteny and partial sequence similarity with the mouse lncRNA, Mrhl. The human homolog, Hmrhl, transcribed from intron 14 of phkb gene, is 5.5 kb in size, expressed in all tissues examined and is associated with chromatin. Analysis of Hmrhl locus using ENCODE database revealed that it exhibits hallmarks of enhancers like the open chromatin configuration, binding of transcription factors, enhancer specific histone signature etc. in the K562 Chronic Myelogenous Leukemia (CML) cells. We compared the expression of Hmrhl in the normal lymphoblast cell line, GM12878, with that of K562 cells and lymphoma samples and show that it is highly upregulated in leukemia as well as several cases of lymphoma. Further, we validated the enhancer properties of Hmrhl locus in K562 cells with the help of ChIP-qPCR and Luciferase assay. Moreover, siRNA mediated down-regulation of Hmrhl in K562 cells leads to a concomitant down regulation of its parent gene, phkb, showing that Hmrhl functions as an enhancer RNA and positively regulates its host gene, phkb, in chronic myelogenous leukemia. This study is significant in view of the fact that a better understanding of mechanism of gene regulation under normal conditions and its perturbation in cancer could in turn help in its therapeutic intervention through molecular medicine/RNA based drug discovery.
| S-EPMC6926186 | biostudies-literature
Project description:Using a CML mouse model, we identified differences in gene expression between leukemic compared with non-leukemic LTHSC, including increased expression of the thrombopoietin (THPO) receptor MPL. LTHSC expressing high levels of MPL showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro, and increased leukemogenic capacity in vivo compared to LTHSC with low MPL expression. Although both G0 and S-phase subpopulations were increased in MPL expressing LTHSC, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSC resulted in reduced THPO-induced JAK/STAT signaling and leukemogenic potential. Similar observations were made with LTHSC from CML patients. MPL expressing LTHSC demonstrated reduced sensitivity to BCR-ABL TKI treatment but demonstrated increased sensitivity to JAK inhibitors. Our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSC, and suggest that MPL-expressing CML stem cells are critical targets for therapy.
2016-06-01 | GSE76123 | GEO
Project description:Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/?-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.
| S-EPMC5096815 | biostudies-other
Project description:Using a CML mouse model, we identified differences in gene expression between leukemic compared with non-leukemic LTHSC, including increased expression of the thrombopoietin (THPO) receptor MPL. LTHSC expressing high levels of MPL showed enhanced JAK/STAT signaling and proliferation in response to THPO in vitro, and increased leukemogenic capacity in vivo compared to LTHSC with low MPL expression. Although both G0 and S-phase subpopulations were increased in MPL expressing LTHSC, LSC capacity was restricted to quiescent cells. Inhibition of MPL expression in CML LTHSC resulted in reduced THPO-induced JAK/STAT signaling and leukemogenic potential. Similar observations were made with LTHSC from CML patients. MPL expressing LTHSC demonstrated reduced sensitivity to BCR-ABL TKI treatment but demonstrated increased sensitivity to JAK inhibitors. Our studies identify MPL expression levels as a key determinant of heterogeneous leukemia-initiating capacity and drug sensitivity of CML LTHSC, and suggest that MPL-expressing CML stem cells are critical targets for therapy. To evaluate heterogeneity in LSC potential, donor LTHSC from SCL-tTA/BCR-ABL mice (200 cells/mouse) were transplanted into a cohort of congenic FVBN mice. Recipient mice were followed for engraftment of donor CML cells and development of CML. LTHSCs were isolated from leukemic and non-leukemic recipient mice and global gene expression was analyzed using RNA-Seq.
2016-06-01 | E-GEOD-76123 | biostudies-arrayexpress
Project description:Chronic myelogenous leukemia (CML) inevitably progresses to a blast phase by mechanisms that are not well understood. The MUC1-C oncoprotein is expressed in CML blasts but not chronic phase cells. The present studies demonstrate that treatment of KU812 and K562 CML cells with a cell-penetrating MUC1-C inhibitor, designated GO-203, is associated with increases in reactive oxygen species (ROS) and depletion of glutathione. GO-203 treatment resulted in the complete downregulation of Bcr-Abl expression and induced cell cycle arrest by a ROS-mediated mechanism that was blocked by the antioxidant N-acetylcysteine. Progression of CML to blast crisis has been linked to dysregulation of Wnt/β-catenin signaling and an arrest of differentiation. The present results show that inhibition of MUC1-C induces ROS-mediated suppression of β-catenin expression and induction of a differentiated myeloid phenotype. Our studies also show that GO-203 treatment is associated with ROS-induced decreases in ATP and loss of survival by late apoptosis/necrosis. These findings demonstrate that inhibition of the MUC1-C oncoprotein in CML cells disrupts redox balance and thereby 1) downregulates expression of both Bcr-Abl and β-catenin and 2) induces terminal myeloid differentiation by ROS-mediated mechanisms.
| S-EPMC3107545 | biostudies-literature
Project description:Transcriptional profiling of human acute myelogenous leukemia (AML) CD34+ cells treated with 5 μM fenretinide. Two timepoints included are 6h, 12h, covering the apoptosis-induction time window of AML CD34+ cells responsing to the fenretinide treatment. We studied gene expression series in human AML CD34+ cells with or without 5 μM fenretinide treatment by cDNA microarray analysis. Several signal transduction pathways are involve, including stress response, NF-kappaB inhibition and p53 inhibition (p<0.05). These findings indicate fenretinide may represent a promising candidate for targeting AML-initiating cells.
2011-11-30 | GSE33243 | GEO
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
Project description:Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5' triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment modalities that are under development. Recent advances have illuminated the complexity of CML, especially within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL because primitive human CML stem cells are not dependent on BCR-ABL. Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML.
| S-EPMC3251313 | biostudies-literature