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Series GSE254285 Query DataSets for GSE254285
Status Public on Jan 31, 2024
Title T cell Immune Escape in Blast Crisis Transformation of Chronic Myeloid Leukemia
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary 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.
 
Overall design Bone marrow (BM) LMPPs from miR-142+/+, miR-142−/−, miR-142+/+BCR-ABL (CP CML), and miR-142−/−BCR-ABL (BC CML) mice (BCR-ABL was induced for two week by tet-off) were sorted for scRNA-seq.
Web link https://doi.org/10.1182/blood-2023-182587
 
Contributor(s) Zhang B, Chen M
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Submission date Jan 26, 2024
Last update date Mar 18, 2024
Contact name WenYong Chen
Organization name City of Hope
Department Department of Cancer Biology and Molecular Medicine
Street address 1500 East Duarte Road
City Duarte
State/province CA
ZIP/Postal code 91010
Country USA
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (10)
GSM8037205 scRNA-seq of WT-LMPP
GSM8037206 scRNA-seq of KO-LMPP
GSM8037207 scRNA-seq of WT-CML-LMPP
This SubSeries is part of SuperSeries:
GSE261822 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
Relations
BioProject PRJNA1069625

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Supplementary file Size Download File type/resource
GSE254285_RAW.tar 925.5 Mb (http)(custom) TAR (of TAR)
SRA Run SelectorHelp
Raw data are available in SRA

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