Shwachman-Diamond syndrome (SDS) is IntroductionShwachman-Diamond syndrome (SDS) 1,2 is an autosomal recessive disease characterized by impaired hematopoiesis, exocrine pancreatic insufficiency, and increased leukemia risk. Additional variable clinical features include skeletal, hepatic, immunologic, and cardiac disorders. 3,4 Most patients with clinical features of SDS harbor biallelic mutations in the SBDS gene located on chromosome 7. 5 SBDS encodes an evolutionarily conserved protein of unknown function. An adjacent conserved pseudogene that shares 97% identity with the SBDS gene is transcribed but fails to encode a full-length protein product. Most SBDS mutations appear to arise from a gene conversion event between the SBDS gene and this adjacent pseudogene. 5 The SBDS mRNA and protein is widely expressed throughout different tissues. [5][6][7][8] Potential functions of the SBDS protein have been inferred from SBDS orthologs. 5,9 The archaeal SBDS ortholog lies within a conserved operon that includes genes involved in RNA processing and protein translation. 10 In transcriptional profiling studies, the yeast ortholog clusters with other RNA processing genes and ribosomal genes. 11 Proteomic analysis of the yeast ortholog protein Ylr022C/Sdo1 suggested an association with other proteins involved in ribosome biogenesis. 12 Genetic interactions between the yeast protein Yhr087w, which shares structural homology with the N-terminal domain of SBDS, and other genes involved in RNA and rRNA processing have been described. 13 In phylogenetic profiling studies, SBDS clustered with other genes involved in RNA metabolism or translation. 9 In support of these findings, we have previously shown that human SBDS is enriched in the nucleolus, the primary cellular site of ribosome biosynthesis. 7 Recently, a role for Sdo1 in 60S ribosomal subunit maturation has been described in yeast. 14 Studies in primary tissues from SDS patients are essential for our understanding of human disease pathogenesis. Studies in mice indicate that the absence of SBDS expression is lethal. 6 Although the early truncating SBDS mutation 183TAϾCT is common among SDS patients, no patients homozygous for this mutation have been identified. 5,9 Taken together, current data support the hypothesis that SDS patients harbor at least one hypomorphic SBDS allele. To investigate SBDS function in human disease, we embarked on a study of SBDS protein in human cell systems and in primary cells from SDS patients. Patients, materials, and methods Cell cultureDana-Farber Cancer Institute Institutional Review Board (DFCI IRB)-approved informed consent was obtained from participating patients in accordance with the Declaration of Helsinki. Lymphoblast cell lines and primary fibroblasts were maintained in culture as described previously. 7 All cells were grown in a humidified 5% CO 2 incubator at 37°C. HeLa cells were maintained in culture in Dulbecco modified Eagle medium (DMEM) (Invitrogen, Carlsbad, CA) supplemented with 10% heat-inactivated fetal Submitted Februa...

SUMMARY Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNA interference screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETi’s) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers. BETi’s retarded the growth of BPDCN xenografts, supporting their clinical evaluation in this recalcitrant malignancy.

• GATA2 deficiency-associated bone marrow disorder can present with features that overlap with idiopathic aplastic anemia.• GATA2 marrows have severely decreased hematogones, monocytes, NK cells, and B cells; variable dysplasia; and clonal cytogenetic abnormalities.Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported in a minority of patients with congenital neutropenia and aplastic anemia (AA). The bone marrow (BM) from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia. Distinguishing GATA2 patients from those with AA is critical for selecting appropriate therapy. We compared the BM flow cytometric, morphologic, and cytogenetic features of 28 GATA2 patients with those of 32 patients being evaluated for idiopathic AA. The marrow of GATA2 patients had severely reduced monocytes, B cells, and NK cells; absent hematogones; and inverted CD4:CD8 ratios. Atypical megakaryocytes and abnormal cytogenetics were more common in GATA2 marrows. CD34 1 cells were comparably reduced in GATA2 and AA. Using these criteria, we prospectively identified 4 of 32 patients with suspected AA who had features suspicious for GATA2 mutations, later confirmed by DNA sequencing. Our results show that routine BM flow cytometry, morphology, and cytogenetics in patients who present with cytopenia(s) can identify patients for whom GATA2 sequencing is indicated. (Blood. 2015;125(1):56-70)

Primary gastrointestinal (GI) T-and NK-cell lymphomas are usually aggressive neoplasms associated with high morbidity and mortality. Over the past two decades, however, cases of primary GI lymphoproliferative disorders (LPDs) or lymphomas of T-or NK-cell derivation with indolent behavior have been reported. These LPDs are rare and they can be challenging to diagnose as they share clinical and pathological features with both, inflammatory disorders and aggressive T-and NK-cell lymphomas. Primary, indolent clonal T-cell proliferations of the GI tract, which can be CD4+, CD8+ or CD4À CD8À, have been included as a provisional entity in the newly revised World Health Organization (WHO) classification of lymphoid neoplasms and designated 'indolent T-cell LPD of the GI tract'. It is currently unclear whether the indolent NK-cell LPDs represent reactive or neoplastic proliferations. In this review, we describe the clinical, morphologic, immunophenotypic and genetic features of indolent GI T-and NK-cell LPDs and provide guidance in differentiating them from other inflammatory and neoplastic diseases. We believe that greater awareness of these LPDs amongst physicians and the research community will lead to timely and accurate diagnoses, stimulate investigations into the pathogenetic mechanisms underlying different entities thereby enhancing our understanding of disease biology and enable the development of effective therapeutic regimens.

SummaryImpairment of ribosome biogenesis or function characterizes several of the inherited bone marrow failure syndromes: Diamond-Blackfan anaemia, dyskeratosis congenita (DC), Shwachman-Diamond syndrome and cartilage-hair hypoplasia. These syndromes exhibit overlapping but distinct clinical phenotypes and each disorder involves different aspects of ribosomal biogenesis. The clinical characteristics of each syndrome are briefly reviewed. Molecular studies of ribosome biogenesis and function in each of these syndromes are discussed. Models of how impairment of ribosomal pathways might affect haematopoiesis and tumorigenesis are explored.

The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.

Despite enormous advances in our understanding of aggressive lymphomas, it is clear that progress in the peripheral T-cell lymphomas (PTCL) has lagged well behind other B-cell malignancies. Although there are many reasons for this, the one commonly cited notes that the paradigms for diffuse large B-cell lymphoma (DLBCL) were merely applied to all patients with PTCL, the classic "one-size-fits-all" approach. Despite these challenges, progress is being made. Recently, the FDA has approved four drugs for patients with relapsed/refractory PTCL over the past 5 years, and if one counts the recent Japanese approval of the anti-CCR4 monoclonal antibody for patients with adult T-cell leukemia/ lymphoma, five drugs have been approved worldwide. These efforts have led to the initiation of no fewer than four randomized clinical studies exploring the integration of these new agents into standard CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone)-based chemotherapy regimens for patients with newly diagnosed PTCL. In addition, a new wave of studies are exploring the merits of novel drug combinations in the disease, an effort to build on the obvious single-agent successes. What has emerged most recently is the recognition that the PTCL may be a disease-characterized by epigenetic dysregulation, which may help explain its sensitivity to histone deacetylase (HDAC) inhibitors, and open the door for even more creative combination approaches. Nonetheless, advances made over a relatively short period of time are changing how we now view these diseases and, hopefully, have poised us to finally improve its prognosis.

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