Gene expression changes associated with progression of Irf8–/– CML-like disease into blast crisis after β-catenin activation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE49054 | GEO | 2013/09/26
SECONDARY ACCESSION(S): PRJNA213468
REPOSITORIES: GEO
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Project description:Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics, we observed that compound constitutive activation of M-NM-2-catenin and deletion of Irf8 results in progression of CML-like disease into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and accumulation of Imatinib-resistant LICs in GMP-like populations. We found that progression of the disease is tightly connected to the magnitude of gene expression and that activated M-NM-2-catenin enhances a pre-existing Irf8-deficient gene signature that was defined as a M-bM-^@M-^\progression specific signatureM-bM-^@M-^] (PSS). We identified M-NM-2-catenin as an amplifier of disease progression and as a critical step in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for M-NM-2-catenin-driven leukemia and imply both factors as targets in combinatorial therapy. We used microarrays to identify the gene expression signature in GMPs underlying CML-like disease progression and identified distinct classes of up- and down-regulated genes during this process defined as a M-bM-^@M-^\progression specific signature (PSS)M-bM-^@M-^]. GMP populations were sorted from three to four independent pools of control MxCreM-bM-^@M-^SCtnnb1(Ex3)fl/+, Ctnnb1(Ex3)M-bM-^HM-^F/+, Irf8M-bM-^@M-^S/M-bM-^@M-^SCtnnb1(Ex3)fl/+ and Irf8M-bM-^@M-^S/M-bM-^@M-^SCtnnb1(Ex3)M-bM-^HM-^F/+ mice for RNA extraction and hybridization on Affymetrix Mouse 430_2 chip arrays (MG-430 PM peg arrays; Affymetrix GeneChip). Cells were sorted using FACSAria (BD Biosciences Immunocytometry Systems, San Jose, CA) flow cytometers and GMPs defined as lineage depleted LinM-bM-^@M-^S Sca-1M-bM-^@M-^Sc-Kit+CD34+FcR II/IIIhi population. All mice were treated with 400M-BM-5g polyinosinic-polycytidylic acid (poly(I:C)) (Amersham) on day 0, 3 and 5 to induce M-NM-2-catenin activation (MxCre-dependent excision of Exon3 in the M-NM-2-catenin gene). Harvesting of bone marrow cells were performed 10-14 days after the last poly(I:C) injection. We used heterozygous inducible MxCre+Ctnnb1(Ex3)fl/+ mice because of the dominant effect from a single activated Ctnnb1 allele. To validate excision efficiency, genomic DNA from harvested cells was subjected to PCR, as previously described (Huelsken et al., 2001; Scheller et al., 2006).
2013-09-26 | E-GEOD-49054 | biostudies-arrayexpress
Project description:Gene expression changes associated with progression of Irf8–/– CML-like disease into blast crisis after β-catenin activation
| PRJNA213468 | ENA
Project description:Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. The biological foundation of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (p<10-10) associated with the progression from chronic to blast phase. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML from chronic advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased leukemia blast cells. The genetic signature of advanced phase CML is similar to that of normal CD34+ cells; however, progression also involved novel genes not expressed in normal CD34+ cells. Especially noteworthy is deregulation of the WNT/b-catenin pathway, the decreased expression of both JunB and Fos, and dysregulation of genes under the control of MZF1 and delta EF1 zinc finger transcription factors. Studies of CML patients who relapsed after initially successful treatment with imatinib mesylate demonstrated a gene expression pattern closely related to advanced phase disease. Take together, these data suggest that CML progression begins relative early and before clinical and pathological detection, and features distinct genetic differences compared to normal hematpoetic cells that might provide diagnostic and therapeutic targets. Samples from different phases of CML were hybridized against the pool of chronic phases of samples.
2010-06-11 | E-GEOD-4170 | biostudies-arrayexpress
Project description:Chronic myeloid leukemia (CML) is a hematopoetic stem cell disease with distinct biological and clinical features. The biological foundation of the stereotypical progression from chronic phase through accelerated phase to blast crisis is poorly understood. We used DNA microarrays to compare gene expression in 91 cases of CML in chronic (42 cases), accelerated (17 cases), and blast phases (32 cases). Three thousand genes were found to be significantly (p<10-10) associated with the progression from chronic to blast phase. A comparison of the gene signatures of chronic, accelerated, and blast phases suggest that the progression of chronic phase CML from chronic advanced phase (accelerated and blast crisis) CML is a two-step rather than a three-step process, with new gene expression changes occurring early in accelerated phase before the accumulation of increased leukemia blast cells. The genetic signature of advanced phase CML is similar to that of normal CD34+ cells; however, progression also involved novel genes not expressed in normal CD34+ cells. Especially noteworthy is deregulation of the WNT/b-catenin pathway, the decreased expression of both JunB and Fos, and dysregulation of genes under the control of MZF1 and delta EF1 zinc finger transcription factors. Studies of CML patients who relapsed after initially successful treatment with imatinib mesylate demonstrated a gene expression pattern closely related to advanced phase disease. Take together, these data suggest that CML progression begins relative early and before clinical and pathological detection, and features distinct genetic differences compared to normal hematpoetic cells that might provide diagnostic and therapeutic targets. Keywords: disease state analysis
2006-02-21 | GSE4170 | 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:Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten CML patients. Accumulating evidence suggests that translational control is crucial for cancer development and progression. Here, we performed high throughput CRISPR/Cas9 screening and identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML-BC progression. PABPC1 preferentially improved the translation efficiency of multiple leukemogenic mRNAs with long and highly structured 5' untranslated regions, including BCR-ABL1 and its TKI-resistant mutants, through forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, but did not affect normal hematopoiesis seriously. More importantly, we identified two novel PABPC1 inhibitors, 1,10-Phen and ML324, which inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identified PABPC1 as a selective translation enhancing factor in CML-BC, the genetic or pharmacological inhibition of which overcame TKI resistance and suppressed BC progression in CML.
2024-03-01 | GSE198142 | GEO
Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSC from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSC) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony forming ability and engraftment potential in immunodeficient mice. We found that the N-Cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-Cadherin-mediated adhesion to MSC was associated with increased cytoplasmic N-Cadherin-β-catenin complex formation, as well as enhanced β-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated β-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-Cadherin and the Wnt-β-catenin pathway in protecting CML LSC during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSC to TKI treatment, and suggest new targets for treatment designed to eradicate residual LSC in CML patients.
2013-01-01 | GSE43225 | GEO
Project description:Little is known about the impact of DNA methylation on the evolution/progression of chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. While only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared to controls, ~6,500 differentially methylated CpG sites were found in cells from BC-CML patients. In the majority of affected CpG sites methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes which were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared to CP-CML-derived cells. Several of them are well-known tumor suppressor genes or regulators of cell proliferation. 5-aza-2 -deoxycytidine treatment of CML cells resulted in gene re-expression and in a dose-dependent cell growth reduction. Single nucleotide variants of certain epigenetic modifiers during CML progression were not found. Together, our results demonstrate that methylation changes occur frequently during CML progression and may provide a useful basis for revealing new targets of therapy in advanced CML.
2016-08-01 | E-MTAB-4333 | biostudies-arrayexpress
Project description:Little is known about the impact of DNA methylation on the evolution/progression of chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. While only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared to controls, ~6,500 differentially methylated CpG sites were found in cells from BC-CML patients. In the majority of affected CpG sites methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes which were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared to CP-CML-derived cells. Several of them are well-known tumor suppressor genes or regulators of cell proliferation. 5-aza-2 -deoxycytidine treatment of CML cells resulted in gene re-expression and in a dose-dependent cell growth reduction. Single nucleotide variants of certain epigenetic modifiers during CML progression were not found. Together, our results demonstrate that methylation changes occur frequently during CML progression and may provide a useful basis for revealing new targets of therapy in advanced CML.
2016-08-01 | E-MTAB-4341 | biostudies-arrayexpress
Project description:Background MicroRNAs are important regulators of transcription in hematopoiesis. Their expression deregulations were described in association with pathogenesis of some hematological malignancies. This study provides integrated microRNA expression profiling at different phases of chronic myeloid leukemia (CML) with the aim to select CML specific miRNAs and find new possible biomarkers. The functions of in silico filtered targets are in this report annotated and discussed in relation to CML pathogenesis. Results Using microarrays we identified differential expression profiles of 49 miRNAs in CML patients at diagnosis, in hematological relapse, therapy failure, blast crisis and major molecular response. The expression deregulation of miR-150, miR-20a, miR-17, miR-19a, miR-103, miR-144, miR-155, miR-181a, miR-221 and miR-222 in CML was confirmed by real-time quantitative PCR and in silico analyses identified targeted genes of these miRNAs encoding proteins that are involved in cell cycle, growth inhibition, MAPK, ErBb, transforming growth factor beta and p53 signaling pathways that are related to CML. Validated miR-150 decreased levels were detected in patients at diagnosis, in blast crisis and 67% of hematological relapses and showed significant negative correlation with miR-150 proved target MYB and with BCR-ABL transcript level. Conclusions This study revealed microRNAs that may be related to the CML pathogenesis and may reflect transformation from chronic to accelerated phases. The obtained expression patterns in peripheral blood total leukocytes during the course of CML suggest specific miRNAs as possible biomarkers. The annotated functions of in silico filtered targets of selected miRNAs outline mechanisms whereby microRNAs may be involved in CML pathogenesis. Twenty four patient samples of total leukocytes from peripheral blood were used to prepare pools representing different CML phases for microarray analysis: diagnosis (n=5, Dg), major molecular response (n=5, MMR), therapy failure (n=5, TF), hematological relapse (n=5, Hr), and blast crisis (n=4, BC). Eleven healthy donors of age median 60 (range 45 - 78) and man/woman ratio 3/2 following CML incidence were used to create a control pool.
2011-05-10 | E-GEOD-26260 | biostudies-arrayexpress