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Various myeloid neoplasms, including the myelodysplastic syndromes (MDS), bear a certain risk of progression to secondary acute myeloid leukemia (sAML). The evolution from low-risk to high-risk MDS and finally to sAML suggests that leukemogenesis is a multistep process. However, even before an overt neoplasm, such as an MDS, develops, “prediagnostic” clonal conditions may be identified. With the advent of large-scale genomic screens, such conditions may be detected quite frequently and early in apparently healthy individuals. Recent data suggest that these conditions increase with age and are indeed associated with an increased risk of the occurrence of MDS or another myeloid neoplasm. In other patients, unexplained cytopenia may be detected and may precede MDS. More recently, diagnostic criteria for potential pre-MDS conditions, including idiopathic cytopenia of uncertain significance and clonal hematopoiesis with indeterminate potential, have been proposed. The current article provides an overview of pre-MDS states and related criteria through which these conditions can be discriminated from each other and from MDS. In addition, the clinical implications and management of pre-MDS states are discussed.

This article provides an overview of recent developments concerning the physiology and pathobiology of mast cells and discusses current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis. Mast cells, which are present in most tissues, mature in situ from hematopoietic progenitors and acquire unique features of local effector cells. These features vary, depending on the tissue microenvironment. This article provides an overview of recent developments concerning the physiology and pathobiology of mast cells. We discuss current diagnostic and therapeutic approaches to mast-cell disorders, with an emphasis on mastocytosis. Physiology and Pathophysiology of Mast Cells Mast cells develop from hematopoietic progenitors in response to stem-cell factor (KIT ligand), which is the ligand of the CD117 transmembrane tyrosine kinase receptor, encoded by KIT . CD117 regulates the growth, migration, . . .

STAT3 and STAT5 proteins are oncogenic downstream mediators of the JAK–STAT pathway. Deregulated STAT3 and STAT5 signaling promotes cancer cell proliferation and survival in conjunction with other core cancer pathways. Nuclear phosphorylated STAT3 and STAT5 regulate cell-type-specific transcription profiles via binding to promoter elements and exert more complex functions involving interaction with various transcriptional coactivators or corepressors and chromatin remodeling proteins. The JAK–STAT pathway can rapidly reshape the chromatin landscape upon cytokine, hormone, or growth factor stimulation and unphosphorylated STAT proteins also appear to be functional with respect to regulating chromatin accessibility. Notably, cancer genome landscape studies have implicated mutations in various epigenetic modifiers as well as the JAK–STAT pathway as underlying causes of many cancers, particularly acute leukemia and lymphomas. However, it is incompletely understood how mutations within these pathways can interact and synergize to promote cancer. We summarize the current knowledge of oncogenic STAT3 and STAT5 functions downstream of cytokine signaling and provide details on prerequisites for DNA binding and gene transcription. We also discuss key interactions of STAT3 and STAT5 with chromatin remodeling factors such as DNA methyltransferases, histone modifiers, cofactors, corepressors, and other transcription factors.

Midostaurin is a multikinase inhibitor that includes mutant and nonmutant KIT D816V as a target. Its use in patients with advanced systemic mastocytosis, including mast-cell leukemia, produced responses in 60%, with a median overall survival of 28.7 months. Systemic mastocytosis is a myeloid neoplasm that is caused by the accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. 1 The KIT D816V mutation, which is detected in approximately 90% of patients, encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. 2 , 3 The World Health Organization (WHO) classification of advanced systemic mastocytosis includes aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm (also termed systemic mastocytosis with an associated hematologic non–mast-cell-lineage disease), and mast-cell leukemia (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). 4 Symptoms are caused . . .

BET bromodomain inhibitors are being explored as potential therapeutics in cancer; here, AML cells are shown to evade sensitivity to BET inhibition through rewiring the transcriptional regulation of BRD4 target genes such as MYC in a process that is facilitated by suppression of PRC2 and WNT signalling activation. Emergence of resistance to BET inhibitors BET inhibitors that target bromodomain chromatin readers such as BRD4 are being explored as potential therapeutics in cancer. Two papers published in this issue of Nature identify mechanisms that may be involved in resistance to BET inhibition in models of leukaemia. In an MLL–AF9 model, Mark Dawson and colleagues find that resistance emerges from leukaemic stem cells and is, in part, a consequence of increased Wnt signalling. Johannes Zuber and colleagues find that suppression of the PRC2 complex renders acute myeloid leukaemia cells resistant to BET inhibition by rewiring the transcriptional regulation of BRD4 target genes such as MYC . Wnt signalling is also implicated as a key driver of resistance. Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML) 1 , 2 , bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers 3 , 4 , 5 . While clinical trials have reported single-agent activity in advanced haematological malignancies 6 , mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL–AF9;Nras G12D -driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc . Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.

Eosinophils and their mediators play a crucial role in various reactive states such as bacterial and viral infections, chronic inflammatory disorders, and certain hematologic malignancies. Depending on the underlying pathology, molecular defect(s), and the cytokine- and mediator-cascades involved, peripheral blood and tissue hypereosinophilia (HE) may develop and may lead to organ dysfunction or even organ damage which usually leads to the diagnosis of a HE syndrome (HES). In some of these patients, the etiology and impact of HE remain unclear. These patients are diagnosed with idiopathic HE. In other patients, HES is diagnosed but the etiology remains unknown — these patients are classified as idiopathic HES. For patients with HES, early therapeutic application of agents reducing eosinophil counts is usually effective in avoiding irreversible organ damage. Therefore, it is important to systematically explore various diagnostic markers and to correctly identify the disease elicitors and etiology. Depending on the presence and type of underlying disease, HES are classified into primary (clonal) HES, reactive HES, and idiopathic HES. In most of these patients, effective therapies can be administered. The current article provides an overview of the pathogenesis of eosinophil-associated disorders, with special emphasis on the molecular, immunological, and clinical complexity of HE and HES. In addition, diagnostic criteria and the classification of eosinophil disorders are reviewed in light of new developments in the field.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

The BCL-2 inhibitor Venetoclax is a promising agent for the treatment of acute myeloid leukemia (AML). However, many patients are refractory to Venetoclax, and resistance develops quickly. ATP-binding cassette (ABC) transporters mediate chemotherapy resistance but their role in modulating the activity of targeted small-molecule inhibitors is unclear. Using CRISPR/Cas9 screening, we find that loss of ABCC1 strongly increases the sensitivity of AML cells to Venetoclax. Genetic and pharmacologic ABCC1 inactivation potentiates the anti-leukemic effects of BCL-2 inhibitors and efficiently re-sensitizes Venetoclax-resistant leukemia cells. Conversely, ABCC1 overexpression induces resistance to BCL-2 inhibitors by reducing intracellular drug levels, and high ABCC1 levels predicts poor response to Venetoclax therapy in patients. Consistent with ABCC1-specific export of glutathionylated substrates, inhibition of glutathione metabolism increases the potency of BCL-2 inhibitors. These results identify ABCC1 and glutathione metabolism as mechanisms limiting efficacy of BCL-2 inhibitors, which may pave the way to development of more effective therapies. BCL-2 inhibition using Venetoclax has emerged as a promising therapy in Acute Myeloid Leukaemia (AML), but primary and acquired resistance is a main limitation of this treatment. Here, the authors show that the ABC transporter ABCC1 (MRP1) together with glutathione, are associated with Venetoclax resistance and represent potential targets to sensitize AML cells to BCL-2 inhibition.

The analytically sensitive detection of D816V in blood and bone marrow is important for diagnosing systemic mastocytosis (SM). Additionally, precise quantification of the D816V variant allele fraction (VAF) is relevant clinically because it helps to predict multilineage involvement and prognosis in cases of advanced SM. Digital PCR (dPCR) is a promising new method for sensitive detection and accurate quantification of somatic mutations. We performed a validation study of dPCR for D816V on 302 peripheral blood and bone marrow samples from 156 patients with mastocytosis for comparison with melting curve analysis after peptide nucleic acid-mediated PCR clamping (clamp-PCR) and allele-specific quantitative real-time PCR (qPCR). dPCR showed a limit of detection of 0.01% VAF with a mean CV of 8.5% and identified the mutation in 90% of patients compared with 70% for clamp-PCR ( < 0.001). Moreover, dPCR for D816V was highly concordant with qPCR without systematic deviation of results, and confirmed the clinical value of D816V VAF measurements. Thus, patients with advanced SM showed a significantly higher D816V VAF (median, 2.43%) compared with patients with indolent SM (median, 0.14%; < 0.001). Moreover, dPCR confirmed the prognostic significance of a high D816V VAF regarding survival ( < 0.001). dPCR for D816V provides a high degree of precision and sensitivity combined with the potential for interlaboratory standardization, which is crucial for the implementation of D816V allele burden measurement. Thus, dPCR is suitable as a new method for D816V testing in patients with mastocytosis.

Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.