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237


The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation

Guillamot, Maria; Ouazia, Dahmane; Dolgalev, Igor; Yeung, Stephen T; Kourtis, Nikos; Dai, Yuling; Corrigan, Kate; Zea-Redondo, Luna; Saraf, Anita; Florens, Laurence; Washburn, Michael P; Tikhonova, Anastasia N; Malumbres, Marina; Gong, Yixiao; Tsirigos, Aristotelis; Park, Christopher; Barbieri, Christopher; Khanna, Kamal M; Busino, Luca; Aifantis, Iannis
The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.
PMID: 31406379
ISSN: 1529-2916
CID: 4042092

3D Chromosomal Landscapes in Hematopoiesis and Immunity

Kloetgen, Andreas; Thandapani, Palaniraja; Tsirigos, Aristotelis; Aifantis, Iannis
Epigenetic dysregulation plays a profound role in the pathogenesis of hematological malignancies, which is often the result of somatic mutations of chromatin regulators. Previously, these mutations were largely considered to alter gene expression in two dimensions, by activating or repressing chromatin states; however, research in the last decade has highlighted the increasing impact of the 3D organization of the genome in gene regulation and disease pathogenesis. Here, we summarize the current principles of 3D chromatin organization, how the integrity of the 3D genome governs immune cell development and malignant transformation, as well as how underlying (epi-)genetic drivers of 3D chromatin alterations might act as potential novel therapeutic targets for hematological malignancies.
PMID: 31422902
ISSN: 1471-4981
CID: 4046552

2029 - THE RELAPSED B-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA IMMUNE MICROENVIRONMENT [Meeting Abstract]

Witkowski, M; Dolgalev, I; Evensen, N; Roberts, K; Sreeram, S; Dai, Y; Tikhonova, A; Loomis, C; Mullighan, C; Tsirigos, A; Carroll, W; Aifantis, I
As with most cancer types, there remains a subset of B-cell acute lymphoblastic leukaemia (B-ALL) patients who will relapse and succumb to therapy-resistant disease. It is believed that tumour heterogeneity underpins therapy failure leading to a Darwinian model of clonal evolution, however, such studies do not account for the role of the bone marrow microenvironment in supporting leukaemia survival, progression and escape from treatment. Here, we perform single-cell RNA-Sequencing (scRNA-Seq) to generate a comprehensive map of the primary human B-ALL bone marrow immune microenvironment throughout three distinct stages of the human leukemic disease process: diagnosis, remission and relapse. These studies show extensive re-modelling of the immune microenvironment composition and cell-to-cell interactions throughout the course conventional chemotherapy, and uncover a role for inflammatory leukaemia-associated monocytes in promoting B-ALL pathogenesis in vivo. These monocytic subsets are predictive of Ph+ B-ALL patient event-free survival and when targeted in B-ALL animal models, lead to prolonged disease remission. Our profiling of the human B-ALL bone marrow immune microenvironment provides a greater understanding of the potential extrinsic regulators of B-ALL survival and may highlight previously unknown environmental factors influencing immune-based treatment approaches to high-risk B-ALL.
EMBASE:2002599067
ISSN: 1873-2399
CID: 4060302

Author Correction: The bone marrow microenvironment at single-cell resolution

Tikhonova, Anastasia N; Dolgalev, Igor; Hu, Hai; Sivaraj, Kishor K; Hoxha, Edlira; Cuesta-Domínguez, Álvaro; 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
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 31296938
ISSN: 1476-4687
CID: 3976852

Machine learning and data mining frameworks for predicting drug response in cancer: An overview and a novel in silico screening process based on association rule mining

Vougas, Konstantinos; Sakelaropoulos, Theodore; Kotsinas, Athanassios; Foukas, George-Romanos P; Ntargaras, Andreas; Koinis, Filippos; Polyzos, Alexander; Myrianthopoulos, Vassilis; Zhou, Hua; Narang, Sonali; Georgoulias, Vassilis; Alexopoulos, Leonidas; Aifantis, Iannis; Townsend, Paul A; Sfikakis, Petros; Fitzgerald, Rebecca; Thanos, Dimitris; Bartek, Jiri; Petty, Russell; Tsirigos, Aristotelis; Gorgoulis, Vassilis G
A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs on a personalized basis. The success of such a task largely depends on the ability to develop computational resources that integrate big "omic" data into effective drug-response models. Machine learning is both an expanding and an evolving computational field that holds promise to cover such needs. Here we provide a focused overview of: 1) the various supervised and unsupervised algorithms used specifically in drug response prediction applications, 2) the strategies employed to develop these algorithms into applicable models, 3) data resources that are fed into these frameworks and 4) pitfalls and challenges to maximize model performance. In this context we also describe a novel in silico screening process, based on Association Rule Mining, for identifying genes as candidate drivers of drug response and compare it with relevant data mining frameworks, for which we generated a web application freely available at: https://compbio.nyumc.org/drugs/. This pipeline explores with high efficiency large sample-spaces, while is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. We conclude with future prospects and challenges of applying machine learning based drug response prediction in precision medicine.
PMID: 31374225
ISSN: 1879-016x
CID: 4011592

Targeting mitochondrial structure sensitizes acute myeloid leukemia to Venetoclax treatment

Chen, Xufeng; Glytsou, Christina; Zhou, Hua; Narang, Sonali; Reyna, Denis E; Lopez, Andrea; Sakellaropoulos, Theodore; Gong, Yixiao; Kloetgen, Andreas; Yap, Yoon Sing; Wang, Eric; Gavathiotis, Evripidis; Tsirigos, Aristotelis; Tibes, Raoul; Aifantis, Iannis
The BCL-2 family plays important roles in acute myeloid leukemia (AML). Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for the treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
PMID: 31048321
ISSN: 2159-8290
CID: 3854932

Splicing the innate immune signalling in leukaemia

Guillamot, Maria; Aifantis, Iannis
PMID: 31011166
ISSN: 1476-4679
CID: 3821442

The bone marrow microenvironment at single-cell resolution

Tikhonova, Anastasia N; Dolgalev, Igor; Hu, Hai; Sivaraj, Kishor K; Hoxha, Edlira; Cuesta-Domínguez, Álvaro; 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

Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia

Wang, Eric; Lu, Sydney X; Pastore, Alessandro; Chen, Xufeng; Imig, Jochen; Chun-Wei Lee, Stanley; Hockemeyer, Kathryn; Ghebrechristos, Yohana E; Yoshimi, Akihide; Inoue, Daichi; Ki, Michelle; Cho, Hana; Bitner, Lillian; Kloetgen, Andreas; Lin, Kuan-Ting; Uehara, Taisuke; Owa, Takashi; Tibes, Raoul; Krainer, Adrian R; Abdel-Wahab, Omar; Aifantis, Iannis
RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.
PMID: 30799057
ISSN: 1878-3686
CID: 3721572

Impaired Expression of Rearranged Immunoglobulin Genes and Premature p53 Activation Block B Cell Development in BMI1 Null Mice

Cantor, David J; King, Bryan; Blumenberg, Lili; DiMauro, Teresa; Aifantis, Iannis; Koralov, Sergei B; Skok, Jane A; David, Gregory
B cell development is a highly regulated process that requires stepwise rearrangement of immunoglobulin genes to generate a functional B cell receptor (BCR). The polycomb group protein BMI1 is required for B cell development, but its function in developing B cells remains poorly defined. We demonstrate that BMI1 functions in a cell-autonomous manner at two stages during early B cell development. First, loss of BMI1 results in a differentiation block at the pro-B cell to pre-B cell transition due to the inability of BMI1-deficient cells to transcribe newly rearranged Igh genes. Accordingly, introduction of a pre-rearranged Igh allele partially restored B cell development in Bmi1-/- mice. In addition, BMI1 is required to prevent premature p53 signaling, and as a consequence, Bmi1-/- large pre-B cells fail to properly proliferate. Altogether, our results clarify the role of BMI1 in early B cell development and uncover an unexpected function of BMI1 during VDJ recombination.
PMID: 30605667
ISSN: 2211-1247
CID: 3562892