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The bone marrow microenvironment at single-cell resolution
Tikhonova, Anastasia N; Dolgalev, Igor; Hu, Hai; Sivaraj, Kishor K; Hoxha, Edlira; Cuesta-DomÃnguez, Ãlvaro; Pinho, Sandra; Akhmetzyanova, Ilseyar; Gao, Jie; Witkowski, Matthew; Guillamot, Maria; Gutkin, Michael C; Zhang, Yutong; Marier, Christian; Diefenbach, Catherine; Kousteni, Stavroula; Heguy, Adriana; Zhong, Hua; Fooksman, David R; Butler, Jason M; Economides, Aris; Frenette, Paul S; Adams, Ralf H; Satija, Rahul; Tsirigos, Aristotelis; Aifantis, Iannis
The bone marrow microenvironment has a key role in regulating haematopoiesis, but its molecular complexity and response to stress are incompletely understood. Here we map the transcriptional landscape of mouse bone marrow vascular, perivascular and osteoblast cell populations at single-cell resolution, both at homeostasis and under conditions of stress-induced haematopoiesis. This analysis revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-haematopoietic growth factors, chemokines and membrane-bound ligands. Our studies demonstrate a considerable transcriptional remodelling of niche elements under stress conditions, including an adipocytic skewing of perivascular cells. Among the stress-induced changes, we observed that vascular Notch delta-like ligands (encoded by Dll1 and Dll4) were downregulated. In the absence of vascular Dll4, haematopoietic stem cells prematurely induced a myeloid transcriptional program. These findings refine our understanding of the cellular architecture of the bone marrow niche, reveal a dynamic and heterogeneous molecular landscape that is highly sensitive to stress and illustrate the utility of single-cell transcriptomic data in evaluating the regulation of haematopoiesis by discrete niche populations.
PMID: 30971824
ISSN: 1476-4687
CID: 3809302
Extensive Remodeling of the Immune Microenvironment in B Cell Acute Lymphoblastic Leukemia
Witkowski, Matthew T; Dolgalev, Igor; Evensen, Nikki A; Ma, Chao; Chambers, Tiffany; Roberts, Kathryn G; Sreeram, Sheetal; Dai, Yuling; Tikhonova, Anastasia N; Lasry, Audrey; Qu, Chunxu; Pei, Deqing; Cheng, Cheng; Robbins, Gabriel A; Pierro, Joanna; Selvaraj, Shanmugapriya; Mezzano, Valeria; Daves, Marla; Lupo, Philip J; Scheurer, Michael E; Loomis, Cynthia A; Mullighan, Charles G; Chen, Weiqiang; Rabin, Karen R; Tsirigos, Aristotelis; Carroll, William L; Aifantis, Iannis
A subset of B cell acute lymphoblastic leukemia (B-ALL) patients will relapse and succumb to therapy-resistant disease. The bone marrow microenvironment may support B-ALL progression and treatment evasion. Utilizing single-cell approaches, we demonstrate B-ALL bone marrow immune microenvironment remodeling upon disease initiation and subsequent re-emergence during conventional chemotherapy. We uncover a role for non-classical monocytes in B-ALL survival, and demonstrate monocyte abundance at B-ALL diagnosis is predictive of pediatric and adult B-ALL patient survival. We show that human B-ALL blasts alter a vascularized microenvironment promoting monocytic differentiation, while depleting leukemia-associated monocytes in B-ALL animal models prolongs disease remission in vivo. Our profiling of the B-ALL immune microenvironment identifies extrinsic regulators of B-ALL survival supporting new immune-based therapeutic approaches for high-risk B-ALL treatment.
PMID: 32470390
ISSN: 1878-3686
CID: 4452012
Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment
Werba, Gregor; Weissinger, Daniel; Kawaler, Emily A; Zhao, Ende; Kalfakakou, Despoina; Dhara, Surajit; Wang, Lidong; Lim, Heather B; Oh, Grace; Jing, Xiaohong; Beri, Nina; Khanna, Lauren; Gonda, Tamas; Oberstein, Paul; Hajdu, Cristina; Loomis, Cynthia; Heguy, Adriana; Sherman, Mara H; Lund, Amanda W; Welling, Theodore H; Dolgalev, Igor; Tsirigos, Aristotelis; Simeone, Diane M
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. Here, we perform single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we find a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibit similar transcriptional responses to chemotherapy and do not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observe decreased ligand-receptor interactions in treated samples, particularly between TIGIT on CD8 + T cells and its receptor on cancer cells, and identify TIGIT as the major inhibitory checkpoint molecule of CD8 + T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.
PMCID:9925748
PMID: 36781852
ISSN: 2041-1723
CID: 5427092
Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma
Dolgalev, Igor; Zhou, Hua; Murrell, Nina; Le, Hortense; Sakellaropoulos, Theodore; Coudray, Nicolas; Zhu, Kelsey; Vasudevaraja, Varshini; Yeaton, Anna; Goparaju, Chandra; Li, Yonghua; Sulaiman, Imran; Tsay, Jun-Chieh J; Meyn, Peter; Mohamed, Hussein; Sydney, Iris; Shiomi, Tomoe; Ramaswami, Sitharam; Narula, Navneet; Kulicke, Ruth; Davis, Fred P; Stransky, Nicolas; Smolen, Gromoslaw A; Cheng, Wei-Yi; Cai, James; Punekar, Salman; Velcheti, Vamsidhar; Sterman, Daniel H; Poirier, J T; Neel, Ben; Wong, Kwok-Kin; Chiriboga, Luis; Heguy, Adriana; Papagiannakopoulos, Thales; Nadorp, Bettina; Snuderl, Matija; Segal, Leopoldo N; Moreira, Andre L; Pass, Harvey I; Tsirigos, Aristotelis
Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.
PMCID:10632519
PMID: 37938580
ISSN: 2041-1723
CID: 5609852
Connecting the Dots: Resolving the Bone Marrow Niche Heterogeneity
Dolgalev, Igor; Tikhonova, Anastasia N
Single-cell sequencing approaches have transformed our understanding of stem cell systems, including hematopoiesis and its niche within the bone marrow. Recent reports examined the bone marrow microenvironment at single-cell resolution at steady state, following chemotherapy treatment, leukemic onset, and aging. These rapid advancements significantly informed our understanding of bone marrow niche heterogeneity. However, inconsistent representation and nomenclature among the studies hinder a comprehensive interpretation of this body of work. Here, we review recent reports interrogating bone marrow niche architecture and present an integrated overview of the published datasets.
PMCID:7994602
PMID: 33777933
ISSN: 2296-634x
CID: 4830472
Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression
Cimmino, Luisa; Dolgalev, Igor; Wang, Yubao; Yoshimi, Akihide; Martin, Gaelle H; Wang, Jingjing; Ng, Victor; Xia, Bo; Witkowski, Matthew T; Mitchell-Flack, Marisa; Grillo, Isabella; Bakogianni, Sofia; Ndiaye-Lobry, Delphine; Martin, Miguel Torres; Guillamot, Maria; Banh, Robert S; Xu, Mingjiang; Figueroa, Maria E; Dickins, Ross A; Abdel-Wahab, Omar; Park, Christopher Y; Tsirigos, Aristotelis; Neel, Benjamin G; Aifantis, Iannis
Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and alpha-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer.
PMCID:5755977
PMID: 28823558
ISSN: 1097-4172
CID: 2676732
Prognostic relevance of integrated genetic profiling in acute myeloid leukemia
Patel, Jay P; Gonen, Mithat; Figueroa, Maria E; Fernandez, Hugo; Sun, Zhuoxin; Racevskis, Janis; Van Vlierberghe, Pieter; Dolgalev, Igor; Thomas, Sabrena; Aminova, Olga; Huberman, Kety; Cheng, Janice; Viale, Agnes; Socci, Nicholas D; Heguy, Adriana; Cherry, Athena; Vance, Gail; Higgins, Rodney R; Ketterling, Rhett P; Gallagher, Robert E; Litzow, Mark; van den Brink, Marcel R M; Lazarus, Hillard M; Rowe, Jacob M; Luger, Selina; Ferrando, Adolfo; Paietta, Elisabeth; Tallman, Martin S; Melnick, Ari; Abdel-Wahab, Omar; Levine, Ross L
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. METHODS: We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. RESULTS: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). CONCLUSIONS: We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
PMCID:3545649
PMID: 22417203
ISSN: 0028-4793
CID: 306772
ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer
Deng, Jiehui; Thennavan, Aatish; Dolgalev, Igor; Chen, Ting; Li, Jie; Marzio, Antonio; Poirier, John T; Peng, David; Bulatovic, Mirna; Mukhopadhyay, Subhadip; Silver, Heather; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Han, Han; Li, Fei; Li, Shuai; Ding, Hailin; Hu, Hai; Pan, Yuanwang; Weerasekara, Vajira; Jiang, Baishan; Wang, Eric S; Ahearn, Ian; Philips, Mark; Papagiannakopoulos, Thales; Tsirigos, Aristotelis; Rothenberg, Eli; Gainor, Justin; Freeman, Gordon J; Rudin, Charles M; Gray, Nathanael S; Hammerman, Peter S; Pagano, Michele; Heymach, John V; Perou, Charles M; Bardeesy, Nabeel; Wong, Kwok-Kin
PMCID:8205437
PMID: 34142094
ISSN: 2662-1347
CID: 4917722
An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup
Gower, Mark; Li, Ximing; Aguilar-Navarro, Alicia G; Lin, Brian; Fernandez, Minerva; Edun, Gibran; Nader, Mursal; Rondeau, Vincent; Arruda, Andrea; Tierens, Anne; Eames Seffernick, Anna; Pölönen, Petri; Durocher, Juliette; Wagenblast, Elvin; Yang, Lin; Lee, Ho Seok; Mullighan, Charles G; Teachey, David; Rashkovan, Marissa; Tremblay, Cedric S; Herranz, Daniel; Itkin, Tomer; Loghavi, Sanam; Dick, John E; Schwartz, Gregory; Perusini, Maria Agustina; Sibai, Hassan; Hitzler, Johann; Gruber, Tanja A; Minden, Mark; Jones, Courtney L; Dolgalev, Igor; Jahangiri, Soheil; Tikhonova, Anastasia N
T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed an integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early T cell precursor ALL, and T/myeloid mixed phenotype acute leukemia. Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers.
PMID: 39742502
ISSN: 1946-6242
CID: 5779592
The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity
Hockemeyer, Kathryn; Sakellaropoulos, Theodore; Chen, Xufeng; Ivashkiv, Olha; Sirenko, Maria; Zhou, Hua; Gambi, Giovanni; Battistello, Elena; Avrampou, Kleopatra; Sun, Zhengxi; Guillamot, Maria; Chiriboga, Luis; Jour, George; Dolgalev, Igor; Corrigan, Kate; Bhatt, Kamala; Osman, Iman; Tsirigos, Aristotelis; Kourtis, Nikos; Aifantis, Iannis
Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.
PMID: 39223375
ISSN: 1476-4679
CID: 5687692