Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
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PROVIDER: EGAS00001005075 | EGA |
REPOSITORIES: EGA
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Project description:A comparison of global gene expression between rigorously defined stem and progenitor cells from patients with chronic myeloid leukaemia (CML) in chronic (CP), accelerated (AP) and blastic (BC) phase and similar populations isolated from normal volunteers. Cryopreserved CD34+ enriched cell populations obtained from patients with CML in CP, AP or BC at diagnosis prior to treatment -- or from normal volunteers -- were thawed and flow sorted into rigorously defined sub-populations (HSC, MPP, CMP, GMP and MEP -- using surface phenotype as described below). Total RNA was obtained and global gene expression measured following hybridisation to Affymetrix HuGene-1_0-st-v1 gene-chips. In total, 3 normal patient samples were compared with 6 CP, 4 AP and 2 BC samples. HSC, CMP, GMP and MEP populations were obtained from all specimens, MPP populations were obtained from normal, AP and BC specimens but not CP specimens.
2013-09-06 | E-GEOD-47927 | 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-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:Chronic myeloid leukemia (CML) may transform from a chronic phase (CP) into blast crisis (BC), which is often incurable. Herein, we report that miR-142 deficit acquired by T lymphocytes contributes to BC transformation by promoting immune escape. We observe that T cells of BC patients lack miR-142 and are fewer and exhausted compared with CP patients. Similarly, BC miR-142−/−/BCR/ABL+/+ mouse presents with T lymphopenia compared with the CP miR-142+/+/BCR/ABL+/+ mouse. In the BC mouse, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into mature T cells and redirects them toward myeloid lineage. The fewer mature T cells in the BC mouse are enriched with exhausted T effectors. MiR-142 deficit, driven by leukemic blasts-secreted inflammatory cytokines (i.e., IL-6), induces T cell hypofunction by preventing the metabolic reprogramming that allows activated T cells to thrive and expand. This ultimately results in an increase in T cell spontaneous apoptosis and BC immune escape. In fact, NSG mice transplanted with BC CML LSKs and miR-142 KO T cells had shorter survival than mice transplanted with BC CML LSKs and miR-142 wild-typewt T cells. Conversely, BC patient-derived xenograft (PDX) mice receiving autologous T cells and synthetic miR-142 lived longer than those receiving autologous T cells and scramble RNA. Combination of tyrosine kinase inhibitors (TKI) plus synthetic miR-142 and/or PD-1 antibody induced a prolonged survival compared to TKI alone, suggesting that harnessing the host immune system with synthetic miR-142 and immunocheckpoint inhibitors along with BCR/ABL inhibition may provide novel therapeutic opportunities.
2024-01-31 | GSE254285 | GEO
Project description:A comparison of global gene expression between rigorously defined stem and progenitor cells from patients with chronic myeloid leukaemia (CML) in chronic (CP), accelerated (AP) and blastic (BC) phase and similar populations isolated from normal volunteers.
2013-09-06 | GSE47927 | 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:Title: Gene expression analysis of indolent and aggressive forms of Chronic Myeloid Leukaemia (CML). Description: Chronic Myeloid Leukaemia presents in chronic phase (CP) and terminates in 'blast crisis'. Despite a common abnormality, the duration of CP is variable. The aim is to compare the gene expression profiles of the indolent and aggressive forms of CML. All samples were taken within 3 months of first diagnosis. Indolent patients were defined by chronic phase CML, duration minimum 7 years. Aggressive patients were defined by chronic phase, duration maximum 3 years.
2013-01-30 | E-MIMR-17 | biostudies-arrayexpress
Project description:We observed that T cells from patients with blast crisis (BC) chronic myeloid leukemia (CML) lacked miR-142 and were fewer and exhausted compared with those from patients with chronic phase (CP) CML. Accordingly, the BC Mir142−/−BCR/ABL mouse also presented with T lymphopenia compared with the CP Mir142+/+BCR/ABL mouse. The miR-142 deficit impaired thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into mature T cells and redirected them toward myeloid lineage. The fewer mature T cells that emerged from LMPP differentiation in the BC mouse were enriched with exhausted T effectors. Leukemic blasts-secreted inflammatory cytokines (i.e., IL-6) mediated the miR-142 deficit, which in turn prevented the metabolic reprogramming that allows activated T cells to thrive and expand and promoted expression of the exhaustion marker PD-1. Thus, loss of miR-142 expression ultimately resulted in BC immune escape and disease growth. In fact, immunodeficient mice transplanted with BC CML LSKs and miR-142 KO T cells had shorter survival than those transplanted with BC CML LSKs and miR-142 wild-type T cells. Conversely, BC patient-derived xenograft (PDX) mice receiving autologous T cells and synthetic miR-142 mimic lived longer than those receiving autologous T cells and scramble RNA. Combination of tyrosine kinase inhibitors (TKI) plus synthetic miR-142 and/or PD-1 antibody induced a prolonged survival compared to TKI alone, suggesting that harnessing the host immune system with synthetic miR-142 may provide a novel therapeutic approach for BC CML.
2024-03-25 | GSE261798 | GEO
Project description:Chronic myeloid leukemia (CML) epitomizes successful targeted therapy, with 86% of patients in the chronic phase treated with tyrosine kinase inhibitors (TKIs) attaining remission. However, resistance to TKIs occurs during treatment, and patients with resistance to TKIs progress to the acute phase called Blast Crisis (BC), wherein the survival is restricted to 7-11 months. About 80 % of patients in BC are unresponsive to TKIs. This issue can be addressed by identifying a molecular signature which can predict resistance in CML-CP prior to treatment as well as by delineating the molecular mechanism underlying resistance. Herein, we report genomic analysis of CML patients and imatinib-resistant K562 cell line to achieve the same. WGS was performed on imatinib-sensitive and -resistant K562 cells. Library preparation was done by 30x WGS KAPA PCR-Free v2.1 kit, and Illumina HiSeq X sequencer was used for 2 x 150 bp paired-end sequencing. Our study identified accumulation of aberrations on chromosomes 1, 3, 7, 16 and 22 as predictive of occurrence of resistance. Further, recurrent amplification in chromosomal region 8q11.2-12.1 was detected in highly resistant K562 cells as well as CML patients. The genes present in this region were analyzed to understand molecular mechanism of imatinib resistance.
2024-01-01 | E-MTAB-11896 | biostudies-arrayexpress
Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
2023-01-13 | ST002446 | MetabolomicsWorkbench