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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

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

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

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

Computational model of CAR T-cell immunotherapy dissects and predicts leukemia patient responses at remission, resistance, and relapse

Liu, Lunan; Ma, Chao; Zhang, Zhuoyu; Witkowski, Matthew T; Aifantis, Iannis; Ghassemi, Saba; Chen, Weiqiang
BACKGROUND:Adaptive CD19-targeted chimeric antigen receptor (CAR) T-cell transfer has become a promising treatment for leukemia. Although patient responses vary across different clinical trials, reliable methods to dissect and predict patient responses to novel therapies are currently lacking. Recently, the depiction of patient responses has been achieved using in silico computational models, with prediction application being limited. METHODS:) relapse. Real-time CAR T-cell and tumor burden data of 209 patients were collected from clinical studies and standardized with unified units in bone marrow. Parameter estimation was conducted using the stochastic approximation expectation maximization algorithm for nonlinear mixed-effect modeling. RESULTS:relapse. Furthermore, we predicted patient responses by combining the peak and accumulated values of CAR T-cells or by inputting early-stage CAR T-cell dynamics. A clinical trial simulation using virtual patient cohorts generated based on real clinical patient datasets was conducted to further validate the prediction. CONCLUSIONS:Our model dissected the mechanism behind distinct responses of leukemia to CAR T-cell therapy. This patient-based computational immuno-oncology model can predict late responses and may be informative in clinical treatment and management.
PMID: 36600553
ISSN: 2051-1426
CID: 5410022

The impact of inflammation-induced tumor plasticity during myeloid transformation

Yeaton, Anna; Cayanan, Geraldine; Loghavi, Sanam; Dolgalev, Igor; Leddin, Emmett M; Loo, Christian E; Torabifard, Hedieh; Nicolet, Deedra; Wang, Jingjing; Corrigan, Kate; Paraskevopoulou, Varvara; Starczynowski, Daniel T; Wang, Eric; Abdel-Wahab, Omar; Viny, Aaron D; Stone, Richard M; Byrd, John C; Guryanova, Olga A; Kohli, Rahul M; Cisneros, G Andres; Tsirigos, Aristotelis; Eisfeld, Ann-Kathrin; Aifantis, Iannis; Guillamot, Maria
Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation, frequently found in CH and leukemic patients. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single cell transcriptomic profiling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population. The gene signature characteristic of this inflammatory population is associated to poor prognosis in AML patients. Our study illustrates an example of collaboration between a genetic lesion found in CH and inflammation, leading to transformation and the establishment of blood neoplasms.
PMID: 35924979
ISSN: 2159-8290
CID: 5288212

Radium 223 induces transient functional bone marrow toxicity

Parlani, Maria; Boccalatte, Francesco; Yeaton, Anna; Wang, Feng; Zhang, Jianhua; Aifantis, Iannis; Dondossola, Eleonora
Radium 223 (Ra223) is a bone-seeking, alpha-particle-emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of Ra223 hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. In this study we investigate the consequences of Ra223 treatment on bone marrow biology. Ra223 accumulated in bones and induced zonal radiation damage confined at the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by three-dimensional multiphoton microscopy, ex vivo. Flow cytometry and single cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, non-specific Ra223-mediated cytotoxicity on resident populations, including stem, progenitor and mature leukocytes. This was paralleled by a significant decrease of white blood cells and platelets in peripheral blood, which was overcome within 40 days post-treatment. Ra223 exposure did not impair full hematopoietic reconstitution, suggesting that the bone marrow function is not permanently hampered. Our results provide a comprehensive explanation of Ra223 reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting its safety for patients.
PMID: 35177425
ISSN: 1535-5667
CID: 5163582

A RORgammat+ cell instructs gut microbiota-specific Treg cell differentiation

Kedmi, Ranit; Najar, Tariq A; Mesa, Kailin R; Grayson, Allyssa; Kroehling, Lina; Hao, Yuhan; Hao, Stephanie; Pokrovskii, Maria; Xu, Mo; Talbot, Jhimmy; Wang, Jiaxi; Germino, Joe; Lareau, Caleb A; Satpathy, Ansuman T; Anderson, Mark S; Laufer, Terri M; Aifantis, Iannis; Bartleson, Juliet M; Allen, Paul M; Paidassi, Helena; Gardner, James M; Stoeckius, Marlon; Littman, Dan R
The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.
PMID: 36071167
ISSN: 1476-4687
CID: 5332522