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Immune Escape of Chronic Myeloid Leukemia in Blast Crisis: The Cross-over of T cell microRNAs, Metabolism and Exhaustion

ABSTRACT: Immune Escape of Chronic Myeloid Leukemia in Blast Crisis: The Cross-over of T cell microRNAs, Metabolism and Exhaustion

PROVIDER: PRJNA1089107 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28372636_1.fastq.gz	Fastqsanger.gz
	SRR28372636_2.fastq.gz	Fastqsanger.gz
	SRR28372637_1.fastq.gz	Fastqsanger.gz
	SRR28372637_2.fastq.gz	Fastqsanger.gz
	SRR28372638_1.fastq.gz	Fastqsanger.gz

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Immune Escape of Chronic Myeloid Leukemia in Blast Crisis: The Cross-over of T cell microRNAs, Metabolism and Exhaustion

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

T cell Immune Escape in Blast Crisis Transformation of Chronic Myeloid Leukemia

Project description:T cell Immune Escape in Blast Crisis Transformation of Chronic Myeloid Leukemia

| PRJNA1069625 | ENA

T cell Immune Escape in Blast Crisis Transformation of Chronic Myeloid Leukemia

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

Transcription profiling of D34+ BCR-ABL+ cells of CML patients in chronic phase or blast crisis to identify differentially expressed stage-specific genes

Project description:Profiling CD34+ BCR-ABL+ cells of CML patients in chronic phase or blast crisis to identify differentially expressed stage-specific genes.

2006-08-08 | E-MEXP-480 | biostudies-arrayexpress

Gene expression changes associated with progression of Irf8–/– CML-like disease into blast crisis after β-catenin activation

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 β-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 β-catenin enhances a pre-existing Irf8-deficient gene signature that was defined as a “progression specific signature” (PSS). We identified β-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 β-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 “progression specific signature (PSS)”.

2013-09-26 | GSE49054 | GEO

Effect of Sdc1 knockout in mouse blast crisis chronic myeloid leukemia (bcCML) cells

Project description:Effect of Sdc1 knockout in mouse blast crisis chronic myeloid leukemia (bcCML) cells

| PRJNA667784 | ENA

Targeting FLT3-TAZ Signaling to Suppress Drug Resistance in Blast Crisis Chronic Myeloid Leukemia

Project description:Although the development of tyrosine kinase inhibitors (TKIs), including BCR-ABL1 targeted therapies, rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast crisis (BC) progression remains a critical challenge. Here, we elucidate the significance of FLT3 signaling in the acquisition of drug resistance in BC-CML. Mechanistically, FLT3 expression in CML cells activated FLT3-JAK-STAT3-TAZ-TEAD-CD36 pathway, which conferred resistance to wide range of tyrosine kinase inhibitors (TKIs). Remarkably, a subgroup of BC-CML patients who expressed FLT3 showed strong correlation with the prognostic factors of CML independent of recurrent BCR-ABL1 mutations. We demonstrate that combining FLT3 inhibitors with BCR-ABL1 targeted therapies or single treatment with ponatinib can overcome drug resistance and promote cell death in patient-derived FLT3+ BC-CML cells and mouse xenograft models. Our findings reveal the mechanism of FLT3-mediated drug resistance in BC progression and suggest the inclusion of FLT3 as a therapeutic target for this defined group of patients.

2023-11-15 | GSE226360 | GEO

Targeting FLT3-TAZ Signaling to Suppress Drug Resistance in Blast Crisis Chronic Myeloid Leukemia

Project description:Targeting FLT3-TAZ Signaling to Suppress Drug Resistance in Blast Crisis Chronic Myeloid Leukemia

| PRJNA940062 | ENA

Selective translational control by PABPC1 phase separation regulates blast crisis and target therapy resistance of chronic myeloid leukemia

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

Investigating Immune Escape of Chronic Myeloid Leukemia in Blast Crisis by Comparing T cells from miR-142 KO BCR-ABL versus miR-142 WT BCR-ABL mice

Project description:Investigating Immune Escape of Chronic Myeloid Leukemia in Blast Crisis by Comparing T cells from miR-142 KO BCR-ABL versus miR-142 WT BCR-ABL mice

| PRJNA1089161 | ENA

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