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BRAFV600Eaccelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia
- Source :
- Blood Advances; November 2017, Vol. 1 Issue: 24 p2147-2160, 14p
- Publication Year :
- 2017
-
Abstract
- Mutated mitogen-activated protein kinase (MAPK) pathway components promote tumor survival, proliferation, and immune evasion in solid tumors. MAPK mutations occur in hematologic cancers as well, but their role is less clear and few models are available to study this. We developed an in vivo model of disseminated BRAFV600EB-cell leukemia to determine the effects of this mutation on tumor development and immune evasion. Mice with B-cell–restricted BRAFV600Eexpression crossed with the Eµ-TCL1 model of chronic lymphocytic leukemia (CLL) developed leukemia significantly earlier (median, 4.9 vs 8.1 months; P≮ .001) and had significantly shorter lifespan (median, 7.3 vs 12.1 months; P≮ .001) versus BRAF wild-type counterparts. BRAFV600Eexpression did not affect B-cell proliferation but reduced spontaneous apoptosis. BRAFV600E-mutant leukemia produced greater T-cell effects, evidenced by exhaustion immunophenotype and CD44+T-cell percentage, as well as increased expression of PD-L1 on CD11b+cells. Results were confirmed in syngeneic mice engrafted with BRAFV600Eleukemia cells. Furthermore, a BRAFV600E-expressing CLL cell line more strongly inhibited anti-CD3/CD28–induced T-cell proliferation, which was reversed by BRAFV600Einhibition. These results demonstrate the immune-suppressive impact of BRAFV600Ein B-cell leukemias and introduce a new model to develop rational combination strategies targeting both tumor cells and tumor-mediated immune evasion.
Details
- Language :
- English
- ISSN :
- 24739529 and 24739537
- Volume :
- 1
- Issue :
- 24
- Database :
- Supplemental Index
- Journal :
- Blood Advances
- Publication Type :
- Periodical
- Accession number :
- ejs56762623
- Full Text :
- https://doi.org/10.1182/bloodadvances.2017006593