ASXL1 loss cooperates with oncogenic NRAS in mice to reprogram the immune microenvironment and drive leukemic transformation Journal Article
| Authors: | You, X.; Liu, F.; Binder, M.; Vedder, A.; Lasho, T.; Wen, Z.; Gao, X.; Flietner, E.; Rajagopalan, A.; Zhou, Y.; Finke, C.; Mangaonkar, A.; Liao, R.; Kong, G.; Ranheim, E. A.; Droin, N.; Hunter, A. M.; Nikolaev, S.; Balasis, M.; Abdel-Wahab, O.; Levine, R. L.; Will, B.; Nadiminti, K. V. G.; Yang, D.; Geissler, K.; Solary, E.; Xu, W.; Padron, E.; Patnaik, M. M.; Zhang, J. |
| Article Title: | ASXL1 loss cooperates with oncogenic NRAS in mice to reprogram the immune microenvironment and drive leukemic transformation |
| Abstract: | Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations. © 2022 American Society of Hematology |
| Journal Title: | Blood |
| Volume: | 139 |
| Issue: | 7 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-02-17 |
| Start Page: | 1066 |
| End Page: | 1079 |
| Language: | English |
| DOI: | 10.1182/blood.2021012519 |
| PUBMED: | 34699595 |
| PROVIDER: | scopus |
| PMCID: | PMC8854684 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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