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tRNAs are central players in decoding the genetic code linking codons in mRNAs with cognate amino acids during protein synthesis. Recent discoveries have placed tRNAs as key regulators of gene expression during hematopoiesis, especially in hematopoietic stem cell (HSC) maintenance and immune development. These functions have been shown to be influenced by dynamic changes in tRNA expression, post-transcriptional base modifications, tRNA-interacting proteins, and tRNA fragmentation; these events underlie the complexity of tRNA-mediated regulatory events in hematopoiesis. In this review, we discuss these recent findings and highlight how deregulation of tRNA biogenesis can contribute to hematological malignancies. tRNA biogenesis is emerging as an important regulator of human hematopoiesis and immune function. tRNA expression signatures mirror the codon bias of the transcriptome during development of mouse immune cells (CD4+ T cells), coordinating demands of cell type-specific mRNA translation. tRNAs are targets of ribonucleases generating a wide array of tRNA microspecies that act as both cell intrinsic and extrinsic signaling molecules regulating hematopoiesis and immune functions in humans and mouse. Deregulation of tRNA biogenesis can contribute to the pathogenesis of hematological malignancies, offering a new avenue for potential therapeutic intervention in humans. [ABSTRACT FROM AUTHOR]

Ten-eleven-translocation (TET) proteins oxidize 5-methylcytosine (5mC) to form stable or transient modifications (oxi-mCs) in the mammalian genome. Genome-wide mapping and protein interaction studies have shown that 5mC and oxi-mCs have unique distribution patterns and alternative roles in gene expression. In addition, oxi-mCs may interact with specific chromatin regulators, transcription factors and DNA repair proteins to maintain genomic integrity or alter DNA replication and transcriptional elongation rates. In this review we will discuss recent advances in our understanding of how TETs and 5hmC exert their epigenetic function as tumor suppressors by playing alternative roles in transcriptional regulation and genomic stability. [ABSTRACT FROM AUTHOR]

Summary V(D)J recombination relies on the presence of proximal enhancers that activate the antigen receptor (AgR) loci in a lineage- and stage-specific manner. Unexpectedly, we find that both active and inactive AgR enhancers cooperate to disseminate their effects in a localized and long-range manner. Here, we demonstrate the importance of short-range contacts between active enhancers that constitute an Igk super-enhancer in B cells. Deletion of one element reduces the interaction frequency between other enhancers in the hub, which compromises the transcriptional output of each component. Furthermore, we establish that, in T cells, long-range contact and cooperation between the inactive Igk enhancer MiEκ and the active Tcrb enhancer Eβ alters enrichment of CBFβ binding in a manner that impacts Tcrb recombination. These findings underline the complexities of enhancer regulation and point to a role for localized and long-range enhancer-sharing between active and inactive elements in lineage- and stage-specific control. [ABSTRACT FROM AUTHOR]

Summary Transcription factors and chromatin-remodeling complexes are key determinants of embryonic stem cell (ESC) identity. Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-renewal ability and pluripotency of ESCs. BRD4 inhibition resulted in induction of epithelial-to-mesenchymal transition (EMT) markers and commitment to the neuroectodermal lineage while reducing the ESC multidifferentiation capacity in teratoma assays. BRD4 maintains transcription of core stem cell genes such as OCT4 and PRDM14 by occupying their super-enhancers (SEs), large clusters of regulatory elements, and recruiting to them Mediator and CDK9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb), to allow Pol-II-dependent productive elongation. Our study describes a mechanism of regulation of ESC identity that could be applied to improve the efficiency of ESC differentiation. [ABSTRACT FROM AUTHOR]

ARID2 is the most recurrently mutated SWI/SNF complex member in melanoma; however, its tumor-suppressive mechanisms in the context of the chromatin landscape remain to be elucidated. Here, we model ARID2 deficiency in melanoma cells, which results in defective PBAF complex assembly with a concomitant genomic redistribution of the BAF complex. Upon ARID2 depletion, a subset of PBAF and shared BAF-PBAF-occupied regions displays diminished chromatin accessibility and associated gene expression, while BAF-occupied enhancers gain chromatin accessibility and expression of genes linked to the process of invasion. As a function of altered accessibility, the genomic occupancy of melanoma-relevant transcription factors is affected and significantly correlates with the observed transcriptional changes. We further demonstrate that ARID2-deficient cells acquire the ability to colonize distal organs in multiple animal models. Taken together, our results reveal a role for ARID2 in mediating BAF and PBAF subcomplex chromatin dynamics with consequences for melanoma metastasis. [Display omitted] • ARID2 loss results in impaired PBAF complex assembly and BAF genomic redistribution • Altered SWI/SNF dynamics results in chromatin accessibility and TF binding changes • PBAF loss drives an invasive gene expression signature and phenotype in melanoma The tumor-suppressive functions of the SWI/SNF subunit ARID2 remain ill-defined in the context of melanoma. Carcamo et al. demonstrate that, upon ARID2 depletion, the PBAF complex fails to assemble, altering BAF genomic occupancy with consequences on chromatin accessibility, transcription factor binding, and transcriptional changes that promote metastasis. [ABSTRACT FROM AUTHOR]

Summary: The bone marrow (BM) microenvironment is composed of multiple niche cells that, by producing paracrine factors, maintain and regenerate the hematopoietic stem cell (HSC) pool (Morrison and Spradling, 2008). We have previously demonstrated that endothelial cells support the proper regeneration of the hematopoietic system following myeloablation (Butler et al., 2010; Hooper et al., 2009; Kobayashi et al., 2010). Here, we demonstrate that expression of the angiocrine factor Jagged-1, supplied by the BM vascular niche, regulates homeostatic and regenerative hematopoiesis through a Notch-dependent mechanism. Conditional deletion of Jagged-1 in endothelial cells (Jag1 (ECKO) mice) results in a profound decrease in hematopoiesis and premature exhaustion of the adult HSC pool, whereas quantification and functional assays demonstrate that loss of Jagged-1 does not perturb vascular or mesenchymal compartments. Taken together, these data demonstrate that the instructive function of endothelial-specific Jagged-1 is required to support the self-renewal and regenerative capacity of HSCs in the adult BM vascular niche. [Copyright &y& Elsevier]

Summary: V(D)J recombination is essential for generating a diverse array of B and T cell receptors that can recognize and combat foreign antigens. As with any recombination event, tight control is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One important aspect of regulation is directed targeting of the RAG recombinase. Indeed, RAG accumulates at the 3′ end of individual antigen receptor loci poised for rearrangement; however, it is not known whether focal binding is involved in regulating cleavage, and what mechanisms lead to enrichment of RAG in this region. Here, we show that monoallelic looping out of the 3′ end of the T cell receptor α (Tcra) locus, coupled with transcription and increased chromatin/nuclear accessibility, is linked to focal RAG binding and ATM-mediated regulation of monoallelic cleavage on looped-out 3′ regions. Our data identify higher-order loop formation as a key determinant of directed RAG targeting and the maintenance of genome stability. [ABSTRACT FROM AUTHOR]

The D-type cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery in mammalian cells. Cyclin D3 gene is rearranged and the protein is overexpressed in several human lymphoid malignancies. In order to determine the function of cyclin D3 in development and oncogenesis, we generated and analyzed cyclin D3-deficient mice. We found that cyclin D3−/− animals fail to undergo normal expansion of immature T lymphocytes and show greatly reduced susceptibility to T cell malignancies triggered by specific oncogenic pathways. The requirement for cyclin D3 also operates in human malignancies, as knock-down of cyclin D3 inhibited proliferation of acute lymphoblastic leukemias deriving from immature T lymphocytes. These studies point to cyclin D3 as a potential target for therapeutic intervention in specific human malignancies. [Copyright &y& Elsevier]

Pre B-ALL is an aggressive cancer of the blood for which treatment of patients with relapsed and refractory disease remains a challenge. In this issue of Cancer Cell , Geng and colleagues surveyed the activation status of the pre-B cell receptor and comprehensively investigated downstream signaling mechanisms currently targetable with small molecule inhibitors. [ABSTRACT FROM AUTHOR]

A major challenge in cancer treatment is predicting clinical response to anti-cancer drugs on a personalized basis. Using a pharmacogenomics database of 1,001 cancer cell lines, we trained deep neural networks for prediction of drug response and assessed their performance on multiple clinical cohorts. We demonstrate that deep neural networks outperform the current state in machine learning frameworks. We provide a proof of concept for the use of deep neural network-based frameworks to aid precision oncology strategies. • A machine learning (ML) workflow is designed to predict drug response in cancer patients • Deep neural networks (DNNs) surpass current ML algorithms in drug response prediction • DNNs predict drug response and survival in various large clinical cohorts • DNNs capture intricate biological interactions linked to specific drug response pathways Sakellaropoulos et al. designed a machine learning workflow to predict drug response and survival of cancer patients. All pipelines are trained on a large panel of cancer cell lines and tested in clinical cohorts. DNN outperforms other machine learning algorithms by capturing pathways that link gene expression with drug response. [ABSTRACT FROM AUTHOR]

The clinical success of the BH3-mimetic venetoclax has generated increasing interest to target BCL2 family proteins in oncology. In this issue of Cancer Cell , Reyna and colleagues demonstrate the potential of a pharmacological activator of the pro-apoptotic protein BAX to suppress acute myeloid leukemia both alone and together with venetoclax. [ABSTRACT FROM AUTHOR]

Summary 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. Graphical Abstract Highlights • BMI1 is required at the pro-B cell to pre-B cell transition in a cell-autonomous manner • BMI1 promotes the expression of newly rearranged Igh genes in pro-B cells • BMI1 prevents premature p53 activation and enables large pre-B cell proliferation Cantor et al. identify a cell-autonomous role for the polycomb group protein BMI1 in early B cell development. At the pro-B cell to pre-B cell transition, BMI1 promotes the expression of newly rearranged Igh genes in pro-B cells and subsequently prevents premature p53 activation and enables large pre-B cell proliferation. [ABSTRACT FROM AUTHOR]

An aberrant MHC-I antigen presentation pathway has been closely linked to low tumor immunogenicity and immunotherapy resistance. Genetic alteration or reduced expression of MHC-I positive regulators has been observed in certain cancers, but is considered a challenge for the development of targeted therapies. MHC-I modulation by cancer-associated inhibitory mechanisms is becoming an emerging field of study, calling for a search for specific modulators and their underlying biology and function in MHC-I modulation and tumor immunity. A membrane-associated MHC-I inhibitory axis was recently documented, mediating MHC-I ubiquitination and subsequent lysosomal degradation in leukemia and solid cancers. We posit that the future exploration of MHC-I inhibitory pathways and their potential application represents an exciting direction for cancer immunotherapy. Cancer cells efficiently hijack the MHC-I antigen presentation (AP) pathway to escape from immunosurveillance and cause resistance to immunotherapy. Exploring specific mechanisms that actively inhibit MHC-I expression and/or AP in tumors can improve our understanding of immune regulation in cancers and provide potential targets for next-generation cancer immunotherapy. The MHC-I antigen presentation (AP) pathway is key to shaping mammalian CD8+ T cell immunity, with its aberrant expression closely linked to low tumor immunogenicity and immunotherapy resistance. While significant attention has been given to genetic mutations and downregulation of positive regulators that are essential for MHC-I AP, there is a growing interest in understanding how tumors actively evade MHC-I expression and/or AP through the induction of MHC-I inhibitory pathways. This emerging field of study may offer more viable therapeutic targets for future cancer immunotherapy. Here, we explore potential mechanisms by which cancer cells evade MHC-I AP and function and propose therapeutic strategies that might target these MHC-I inhibitors to restore impaired T cell immunity within the tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

Summary T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE. Graphical Abstract Highlights • STIM1 and STIM2 mediate calcium influx in Notch1-induced leukemic T lymphoblasts • Deletion of STIM1 and STIM2 prolongs the survival of mice with T-ALL • Similar leukemic burden but no tissue necrosis in mice with STIM1/STIM2-negative T-ALL • STIM1 and STIM2 control multiple proinflammatory pathways in leukemic T lymphoblasts T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of T cell progenitors affecting children and adults. Saint Fleur-Lominy et al. show that calcium influx mediated by STIM1 and STIM2 promotes the proinflammatory function of leukemic cells and premature death from leukemia. [ABSTRACT FROM AUTHOR]

Vitamin C is an essential dietary requirement for humans. In addition to its known role as an antioxidant, vitamin C is a cofactor for Fe 2+ - and α-ketoglutarate-dependent dioxygenases (Fe 2+ /α-KGDDs) which comprise a large number of diverse enzymes, including collagen prolyl hydroxylases and epigenetic regulators of histone and DNA methylation. Vitamin C can modulate embryonic stem cell (ESC) function, enhance reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs), and hinder the aberrant self-renewal of hematopoietic stem cells (HSCs) through its ability to enhance the activity of either Jumonji C (JmjC) domain-containing histone demethylases or ten-eleven translocation (TET) DNA hydroxylases. Given that epigenetic dysregulation is a known driver of malignancy, vitamin C may play a novel role as an epigenetic anticancer agent. [ABSTRACT FROM AUTHOR]

Protein degradation plays key roles in diverse pathways in cell division, growth and differentiation. Aberrant stabilization of crucial proteins participating in oncogenic pathways is often observed in cancer. The importance of proper protein turnover is exemplified by the SCF Fbxw7 ubiquitin ligase, which is frequently mutated in human cancer, including T cell acute lymphoblastic leukemia. Recent studies have revealed novel substrates of Fbxw7 and shed light on its role on differentiation of stem cells and expansion of stem-cell-like cells driving tumorigenesis. Detailed understanding of the contribution of the Fbxw7-regulated network of proteins in initiation and progression of cancer will facilitate the identification of candidate intervention targets in human cancer. [ABSTRACT FROM AUTHOR]

Genetic approaches to the study of hematopoietic stem cell (HSC) function in their native hosts led to conflicting notions about the rate and lineage spectrum of HSC contribution to hematopoiesis. Our lab has developed a model for inducible labeling and tracing of the most undifferentiated "top-level" adult HSCs in unmanipulated mice. This model revealed a major sustained contribution of adult HSCs to all lineages, confirming HSCs as the ultimate source of adult hematopoiesis in the steady state. Furthermore, clonal tracing showed that originally labeled HSC clones were maintained and contributed to immune cell differentiation. We found that the contribution of HSCs to hematopoiesis in old animals was globally reduced across the entire lineage spectrum, suggesting a global "decoupling" of HSCs from continuous hematopoiesis. The reduced contribution of old HSCs could not be compensated in lymphoid lineages, likely underlying the selective impairment of lymphopoiesis that is a hallmark of aging. We also characterized the impact of oncogenic mutations arising in HSCs on endogenous hematopoiesis. In particular, the leukemogenic KrasG12D mutation dramatically accelerated the contribution of mutation-carrying HSC to all hematopoietic lineages. The acceleration was mediated by KrasG12D-expressing multipotent progenitors (MPP) that rapidly outcompeted normal MPP. Mutation-carrying MPP lacked self-renewal capacity but underwent a profound reprogramming of their transcriptome and physiology. In particular, intravital imaging revealed increased CXCR4-driven motility of mutant progenitors in their bone marrow niche, and the blockade of CXCR4 reduced their expansion in vivo. Thus, transforming mutations facilitate their own spread from stem cells by reprogramming multipotent progenitors, creating a pre-leukemic state via a two-component stem/progenitor circuit. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) residing in the bone marrow generate mature blood cells throughout the life of the organism. This is accomplished by careful regulation of HSC activity to balance quiescence, self-renewal and differentiation. Studies of the molecular mechanisms governing HSC maintenance have mostly focused on the role of signaling and transcriptional processes. However, it has recently been demonstrated that protein regulation via the ubiquitin proteasome system (UPS) is crucial for normal HSC function; the loss of which can lead to transformation and leukemogenesis. The effective use of a general and reversible inhibitor of the UPS, bortezomib, in treating mantle cell lymphoma and multiple myeloma has demonstrated that targeting the UPS has therapeutic potential. Thus, understanding the emerging field of how the UPS regulates HSC activity may lead to novel targets for therapy of leukemia. [ABSTRACT FROM AUTHOR]

TLX1 and TLX3 are two closely-related homeobox transcriptional repressors frequently misexpressed and translocated in T cell acute lymphoblastic leukemia (T-ALL). In this issue of Cancer Cell, Dadi et al. provide new insights into how these factors are recruited by ETS-1 to the TCRα enhancer and actively repress differentiation. [Copyright &y& Elsevier]

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. The 3D chromatin architecture is emerging as an important player in the pathogenesis of hematological malignancies. Normal hematopoiesis and immune cell maturation are accompanied by widespread changes in chromatin compartments, topologically associated domains, and epigenetic features to ensure lineage commitment. Chromatin architectural changes driven by either genetic or epigenetic dysregulation can activate proto-oncogenes by altering regulatory interactions, contributing to tumorigenesis. Genetic mutations in key epigenetic players can drive cancer development by impacting 3D chromatin architecture. [ABSTRACT FROM AUTHOR]

Summary The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL. [ABSTRACT FROM AUTHOR]

Summary Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2’s normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2 , which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis. [ABSTRACT FROM AUTHOR]

The overexpression of microRNA cluster miR-17-92 has been implicated in development of solid tumors and hematological malignancies. The role of miR-17-92 in lymphomagenesis has been extensively investigated; however, because of the developmental defects caused by miR-17-92 dysregulation, its ability to drive tumorigenesis has remained undetermined until recently. Here we demonstrate that overexpression of miR-17-92 in a limited number of hematopoietic cells is sufficient to cause B cell malignancies. In sum, our study provides a novel and physiologically relevant model that exposes the potent ability of miR-17-92 to act as a driver of tumorigenesis. [ABSTRACT FROM AUTHOR]

Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive functions of Notch signaling, and dissect the molecular mechanisms that underlie these functions in hematopoietic cancers and solid tumors. Finally, we link these mechanisms and observations to possible therapeutic strategies targeting the Notch pathway in human cancers. [ABSTRACT FROM AUTHOR]

Summary: The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or attenuation of the p53 response rescues LIC activity and disease progression. Further experiments showed that Fbw7 expression is required for survival and maintenance of human CML LIC. These studies identify a ubiquitin ligase:substrate pair regulating LIC activity, suggesting that targeting of the Fbw7:c-Myc axis is an attractive therapy target in refractory CML. [Copyright &y& Elsevier]

Summary: D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27Kip1 and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3 −/− thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor. [ABSTRACT FROM AUTHOR]

Summary: Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. [ABSTRACT FROM AUTHOR]

Summary: It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. [Copyright &y& Elsevier]

Recent studies provide fresh insight into the mechanisms by which precursor cells are committed to and develop within the T-lymphocyte lineage. Precursor/product studies have identified developmental stages between that of the pluripotent hematopoietic stem cell and thymocytes committed to the T lineage. Specific ligands and signaling pathways interacting with the Notch-1 receptor and its ability to influence commitment within the lymphoid lineage have been described. Although the structural features or putative ligands endowing the pre-TCR with constitutive signaling capacity remain elusive, numerous distal mediators of pre-TCR signaling have been identified. It remains for the future to determine what roles they may have in survival, proliferation, lineage commitment and allelic exclusion of TCR genes. Receptor editing and lineage commitment of αβ T cells still represent controversial topics that need further study. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]