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3D chromatin hubs as regulatory units of identity and survival in human acute leukemia
Gambi, Giovanni; Boccalatte, Francesco; Rodriguez Hernaez, Javier; Lin, Ziyan; Nadorp, Bettina; Polyzos, Alexander; Tan, Jimin; Avrampou, Kleopatra; Inghirami, Giorgio; Kentsis, Alex; Apostolou, Effie; Aifantis, Iannis; Tsirigos, Aristotelis
Cancer progression involves genetic and epigenetic changes that disrupt chromatin 3D organization, affecting enhancer-promoter interactions and promoting growth. Here, we provide an integrative approach, combining chromatin conformation, accessibility, and transcription analysis, validated by in silico and CRISPR-interference screens, to identify relevant 3D topologies in pediatric T cell leukemia (T-ALL and ETP-ALL). We characterize 3D hubs as regulatory centers for oncogenes and disease markers, linking them to biological processes like cell division, inflammation, and stress response. Single-cell mapping reveals heterogeneous gene activation in discrete epigenetic clones, aiding in patient stratification for relapse risk after chemotherapy. Finally, we identify MYB as a 3D hub regulator in leukemia cells and show that the targeting of key regulators leads to hub dissolution, thereby providing a novel and effective anti-leukemic strategy. Overall, our work demonstrates the relevance of studying oncogenic 3D hubs to better understand cancer biology and tumor heterogeneity and to propose novel therapeutic strategies.
PMID: 39719705
ISSN: 1097-4164
CID: 5767452
IFN-γ-producing TH1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease
Wang, Yin-Hu; Li, Wenyi; McDermott, Maxwell; Son, Ga-Yeon; Maiti, George; Zhou, Fang; Tao, Anthony Y; Raphael, Dimitrius; Moreira, Andre L; Shen, Boheng; Vaeth, Martin; Nadorp, Bettina; Chakravarti, Shukti; Lacruz, Rodrigo S; Feske, Stefan
Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (Treg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of Treg cells depend on store-operated Ca2+ entry (SOCE), which is mediated by ORAI1 Ca2+ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3+ Treg cell-specific deletion of Stim1 and Stim2 develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (TH1) and interferon (IFN) signaling. CD4+ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4+ T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4+ T cells from patients with SjD, which indicate enhanced TH1 but reduced memory Treg cell function. Together, our study provides evidence for a critical role of dysfunctional Treg cells and IFN-γ-producing TH1 cells in the pathogenesis of SjD.
PMID: 39693412
ISSN: 1946-6242
CID: 5764522
RAS-mutant leukaemia stem cells drive clinical resistance to venetoclax
Sango, Junya; Carcamo, Saul; Sirenko, Maria; Maiti, Abhishek; Mansour, Hager; Ulukaya, Gulay; Tomalin, Lewis E; Cruz-Rodriguez, Nataly; Wang, Tiansu; Olszewska, Malgorzata; Olivier, Emmanuel; Jaud, Manon; Nadorp, Bettina; Kroger, Benjamin; Hu, Feng; Silverman, Lewis; Chung, Stephen S; Wagenblast, Elvin; Chaligne, Ronan; Eisfeld, Ann-Kathrin; Demircioglu, Deniz; Landau, Dan A; Lito, Piro; Papaemmanuil, Elli; DiNardo, Courtney D; Hasson, Dan; Konopleva, Marina; Papapetrou, Eirini P
Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1-6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte-monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients.
PMID: 39478230
ISSN: 1476-4687
CID: 5747162
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
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
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
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
TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity
Muto, Tomoya; Guillamot, Maria; Yeung, Jennifer; Fang, Jing; Bennett, Joshua; Nadorp, Bettina; Lasry, Audrey; Redondo, Luna Zea; Choi, Kwangmin; Gong, Yixiao; Walker, Callum S; Hueneman, Kathleen; Bolanos, Lyndsey C; Barreyro, Laura; Lee, Lynn H; Greis, Kenneth D; Vasyliev, Nikita; Khodadadi-Jamayran, Alireza; Nudler, Evgeny; Lujambio, Amaia; Lowe, Scott W; Aifantis, Iannis; Starczynowski, Daniel T
Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.
PMID: 35045331
ISSN: 1875-9777
CID: 5131582
Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation
Wang, Eric; Zhou, Hua; Nadorp, Bettina; Cayanan, Geraldine; Chen, Xufeng; Yeaton, Anna H; Nomikou, Sofia; Witkowski, Matthew T; Narang, Sonali; Kloetgen, Andreas; Thandapani, Palaniraja; Ravn-Boess, Niklas; Tsirigos, Aristotelis; Aifantis, Iannis
Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation. Mechanistically, ZFP36L2 interacts with the 3' untranslated region of key myeloid maturation genes, including the ZFP36 paralogs, to promote their mRNA degradation and suppress terminal myeloid cell differentiation. Genetic inhibition of ZFP36L2 restores the mRNA stability of these targeted transcripts and ultimately triggers myeloid differentiation in leukemia cells. Epigenome profiling of several individuals with primary AML revealed enhancer modules near ZFP36L2 that associated with distinct AML cell states, establishing a coordinated epigenetic and post-transcriptional mechanism that shapes leukemic differentiation.
PMID: 33450187
ISSN: 1875-9777
CID: 4747382