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A membrane-associated MHC-I inhibitory axis for cancer immune evasion

Chen, Xufeng; Lu, Qiao; Zhou, Hua; Liu, Jia; Nadorp, Bettina; Lasry, Audrey; Sun, Zhengxi; Lai, Baoling; Rona, Gergely; Zhang, Jiangyan; Cammer, Michael; Wang, Kun; Al-Santli, Wafa; Ciantra, Zoe; Guo, Qianjin; You, Jia; Sengupta, Debrup; Boukhris, Ahmad; Zhang, Hongbing; Liu, Cheng; Cresswell, Peter; Dahia, Patricia L M; Pagano, Michele; Aifantis, Iannis; Wang, Jun
Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.
PMID: 37557169
ISSN: 1097-4172
CID: 5602312

Flow cytometric assessment of leukemia-associated monocytes in childhood B-cell acute lymphoblastic leukemia outcome

Contreras Yametti, Gloria Paz; Evensen, Nikki A; Schloss, Jennifer; Aldebert, Clemence; Duan, Emily; Zhang, Yan; Hu, Jiyuan; Chambers, Tiffany M; Scheurer, Michael E; Teachey, David T; Rabin, Karen R; Raetz, Elizabeth A; Aifantis, Iannis; Carroll, William L; Witkowski, Matthew T
PMID: 37196626
ISSN: 2473-9537
CID: 5505192

Cell-type-specific prediction of 3D chromatin organization enables high-throughput in silico genetic screening

Tan, Jimin; Shenker-Tauris, Nina; Rodriguez-Hernaez, Javier; Wang, Eric; Sakellaropoulos, Theodore; Boccalatte, Francesco; Thandapani, Palaniraja; Skok, Jane; Aifantis, Iannis; Fenyö, David; Xia, Bo; Tsirigos, Aristotelis
Investigating how chromatin organization determines cell-type-specific gene expression remains challenging. Experimental methods for measuring three-dimensional chromatin organization, such as Hi-C, are costly and have technical limitations, restricting their broad application particularly in high-throughput genetic perturbations. We present C.Origami, a multimodal deep neural network that performs de novo prediction of cell-type-specific chromatin organization using DNA sequence and two cell-type-specific genomic features-CTCF binding and chromatin accessibility. C.Origami enables in silico experiments to examine the impact of genetic changes on chromatin interactions. We further developed an in silico genetic screening approach to assess how individual DNA elements may contribute to chromatin organization and to identify putative cell-type-specific trans-acting regulators that collectively determine chromatin architecture. Applying this approach to leukemia cells and normal T cells, we demonstrate that cell-type-specific in silico genetic screening, enabled by C.Origami, can be used to systematically discover novel chromatin regulation circuits in both normal and disease-related biological systems.
PMID: 36624151
ISSN: 1546-1696
CID: 5434302

Mitophagy promotes resistance to BH3 mimetics in acute myeloid leukemia

Glytsou, Christina; Chen, Xufeng; Zacharioudakis, Emmanouil; Al-Santli, Wafa; Zhou, Hua; Nadorp, Bettina; Lee, Soobeom; Lasry, Audrey; Sun, Zhengxi; Papaioannou, Dimitrios; Cammer, Michael; Wang, Kun; Zal, Tomasz; Zal, Malgorzata Anna; Carter, Bing Z; Ishizawa, Jo; Tibes, Raoul; Tsirigos, Aristotelis; Andreeff, Michael; Gavathiotis, Evripidis; Aifantis, Iannis
BH3-mimetics are used as an efficient strategy to induce cell death in several blood malignancies, including acute myeloid leukemia (AML). Venetoclax, a potent BCL-2 antagonist, is used clinically in combination with hypomethylating agents for the treatment of AML. Moreover, MCL-1 or dual BCL-2/BCL-xL antagonists are under investigation. Yet, resistance to single or combinatorial BH3-mimetics therapies eventually ensues. Integration of multiple genome-wide CRISPR/Cas9 screens revealed that loss of mitophagy modulators sensitizes AML cells to various BH3-mimetics targeting different BCL-2 family members. One such regulator is MFN2, whose protein levels positively correlate with drug resistance in patients with AML. MFN2 overexpression is sufficient to drive resistance to BH3-mimetics in AML. Insensitivity to BH3-mimetics is accompanied by enhanced mitochondria-endoplasmic reticulum interactions and augmented mitophagy flux which acts as a pro-survival mechanism to eliminate mitochondrial damage. Genetic or pharmacologic MFN2 targeting synergizes with BH3-mimetics by impairing mitochondrial clearance and enhancing apoptosis in AML.
PMID: 37088914
ISSN: 2159-8290
CID: 5464912

The Role of Inflammation in the Initiation and Progression of Myeloid Neoplasms

Balandrán, Juan Carlos; Lasry, Audrey; Aifantis, Iannis
UNLABELLED:Myeloid malignancies are devastating hematologic cancers with limited therapeutic options. Inflammation is emerging as a novel driver of myeloid malignancy, with important implications for tumor composition, immune response, therapeutic options, and patient survival. Here, we discuss the role of inflammation in normal and malignant hematopoiesis, from clonal hematopoiesis to full-blown myeloid leukemia. We discuss how inflammation shapes clonal output from hematopoietic stem cells, how inflammation alters the immune microenvironment in the bone marrow, and novel therapies aimed at targeting inflammation in myeloid disease. SIGNIFICANCE:Inflammation is emerging as an important factor in myeloid malignancies. Understanding the role of inflammation in myeloid transformation, and the interplay between inflammation and other drivers of leukemogenesis, may yield novel avenues for therapy.
PMID: 37052531
ISSN: 2643-3249
CID: 5536472

Integrative CRISPR Activation and Small Molecule Inhibitor Screening for lncRNA Mediating BRAF Inhibitor Resistance in Melanoma

Shamloo, Sama; Kloetgen, Andreas; Petroulia, Stavroula; Hockemeyer, Kathryn; Sievers, Sonja; Tsirigos, Aristotelis; Aifantis, Ioannis; Imig, Jochen
The incidence of melanoma, being one of the most commonly occurring cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. The conventional targeted therapy is well defined and effective for advanced-stage melanomas for patients not responding to the standard-of-care immunotherapy. However, targeted therapies do not prove to be as effective as patients inevitably develop V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-inhibitor resistance to the respective drugs. Factors which are driving melanoma drug resistance mainly involve mutations in the mitogen-activated protein kinase (MAPK) pathway, e.g., BRAF splice variants, neuroblastoma RAS viral oncogene homolog (NRAS) amplification or parallel survival pathways. However, those mechanisms do not explain all cases of occurring resistances. Therefore, other factors accounting for BRAFi resistance must be better understood. Among them there are long non-coding RNAs (lncRNAs), but these remain functionally poorly understood. Here, we conduct a comprehensive, unbiased, and integrative study of lncRNA expression, coupled with a Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-mediated activation (CRISPRa) and small molecule inhibitor screening for BRAF inhibitor resistance to expand the knowledge of potentially druggable lncRNAs, their function, and pave the way for eventual combinatorial treatment approaches targeting diverse pathways in melanoma.
ISSN: 2227-9059
CID: 5615132

Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion

Battistello, Elena; Hixon, Kimberlee A; Comstock, Dawn E; Collings, Clayton K; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S; Hinkley, Madeline M; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W Nicholas; Witkowski, Matthew T; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall
Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
PMID: 36944333
ISSN: 1097-4164
CID: 5462792

Oncogenic drivers dictate immune control of acute myeloid leukemia

Austin, Rebecca J; Straube, Jasmin; Halder, Rohit; Janardhanan, Yashaswini; Bruedigam, Claudia; Witkowski, Matthew; Cooper, Leanne; Porter, Amy; Braun, Matthias; Souza-Fonseca-Guimaraes, Fernando; Minnie, Simone A; Cooper, Emily; Jacquelin, Sebastien; Song, Axia; Bald, Tobias; Nakamura, Kyohei; Hill, Geoffrey R; Aifantis, Iannis; Lane, Steven W; Bywater, Megan J
Acute myeloid leukemia (AML) is a genetically heterogeneous, aggressive hematological malignancy induced by distinct oncogenic driver mutations. The effect of specific AML oncogenes on immune activation or suppression is unclear. Here, we examine immune responses in genetically distinct models of AML and demonstrate that specific AML oncogenes dictate immunogenicity, the quality of immune response and immune escape through immunoediting. Specifically, expression of NrasG12D alone is sufficient to drive a potent anti-leukemia response through increased MHC Class II expression that can be overcome with increased expression of Myc. These data have important implications for the design and implementation of personalized immunotherapies for patients with AML.
PMID: 37059710
ISSN: 2041-1723
CID: 5464312

An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia

Lasry, Audrey; Nadorp, Bettina; Fornerod, Maarten; Nicolet, Deedra; Wu, Huiyun; Walker, Christopher J; Sun, Zhengxi; Witkowski, Matthew T; Tikhonova, Anastasia N; Guillamot-Ruano, Maria; Cayanan, Geraldine; Yeaton, Anna; Robbins, Gabriel; Obeng, Esther A; Tsirigos, Aristotelis; Stone, Richard M; Byrd, John C; Pounds, Stanley; Carroll, William L; Gruber, Tanja A; Eisfeld, Ann-Kathrin; Aifantis, Iannis
Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive census of the bone marrow immune microenvironment in adult and pediatric patients with AML. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B-cell subtype enriched in patients with high-inflammation AML, as well as an increase in CD8+GZMK+ and regulatory T cells, accompanied by a reduction in T-cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in patients with AML. Addition of the iScore refines current risk stratifications for patients with AML and may enable identification of patients in need of more aggressive treatment. This work provides a framework for classifying patients with AML based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings.
PMID: 36581735
ISSN: 2662-1347
CID: 5409732

Author Correction: An inflammatory state remodels the immune microenvironment and improves risk stratification in acute myeloid leukemia

Lasry, Audrey; Nadorp, Bettina; Fornerod, Maarten; Nicolet, Deedra; Wu, Huiyun; Walker, Christopher J; Sun, Zhengxi; Witkowski, Matthew T; Tikhonova, Anastasia N; Guillamot-Ruano, Maria; Cayanan, Geraldine; Yeaton, Anna; Robbins, Gabriel; Obeng, Esther A; Tsirigos, Aristotelis; Stone, Richard M; Byrd, John C; Pounds, Stanley; Carroll, William L; Gruber, Tanja A; Eisfeld, Ann-Kathrin; Aifantis, Iannis
PMID: 36658429
ISSN: 2662-1347
CID: 5417042