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| 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
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| 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.
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| 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.
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| Web link |
https://doi.org/10.1182/blood-2023-182587
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| Contributor(s) |
Zhang B, Chen M |
| Citation missing |
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| |
| Submission date |
Jan 26, 2024 |
| Last update date |
Mar 18, 2024 |
| Contact name |
Elizabeth Budde |
| Organization name |
City of Hope
|
| Department |
PH Hematology
|
| Street address |
1500 E Duarte Rd
|
| City |
Duarte |
| State/province |
CA |
| ZIP/Postal code |
91010 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (10)
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| 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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