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T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53 -wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53 -wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models. T- and NK-cell lymphomas (TCL) are a group of lymphoid malignancies characterized by poor prognosis, but the absence of appropriate pre-clinical models has hampered the development of effective therapies. Here the authors establish several pre-clinical models and identify vulnerabilities that could be further exploited to treat patients afflicted by these diseases.

Susceptibility to cancer is heritable, but much of this heritability remains unexplained. Some ‘missing’ heritability may be mediated by epigenetic changes in the parental germ line that do not involve transmission of genetic variants from parent to offspring. We report that deletion of the chromatin regulator Kdm6a (Utx) in the paternal germ line results in elevated tumor incidence in genetically wild type mice. This effect increases following passage through two successive generations of Kdm6a male germline deletion, but is lost following passage through a wild type germ line. The H3K27me3 mark is redistributed in sperm of Kdm6a mutants, and we define approximately 200 H3K27me3-marked regions that exhibit increased DNA methylation, both in sperm of Kdm6a mutants and in somatic tissue of progeny. Hypermethylated regions in enhancers may alter regulation of genes involved in cancer initiation or progression. Epigenetic changes in male gametes may therefore impact cancer susceptibility in adult offspring. Many diseases, such as certain cancers, run in families. Often, this is because several related individuals inherit a version of a gene that is faulty and causes the condition. But in a number of families with high rates of cancer, scientists are unable to pinpoint such disease-causing gene versions. Instead, it is possible that individuals inherit healthy genes that are not read and interpreted correctly by the cells. This could be because of epigenetic changes, modifications that do not alter the genetic code but can instead turn genes on or off temporarily by adding or removing certain marks on the genetic information. For a long time, researchers thought that epigenetic changes could not be passed from one generation to the next, but recent studies have revealed this is actually possible. However, it had never been shown that this could be associated with having a higher risk of developing cancer. Now, Lesch et al. show that epigenetic changes passed from male mice to their offspring make these animals more likely to develop tumors than typical mice. In the experiments, mouse sperm were genetically engineered to have a mutation in a gene called Kdm6a (also called Utx by cancer researchers), which controls the placement of epigenetic marks. Male mice carrying a defective Kdm6a gene were then mated to normal females. The resulting offspring developed more tumors than mice produced from normal sperm, even though they inherited a normal copy of the Kdm6a gene from their mother. Lesch et al. also show that the offspring have epigenetic marks similar to the ones found in the mutant sperm. This may change whether genes that stop or promote tumor formation are switched on or off. Certain cancer treatments work by targeting epigenetic changes. The results by Lesch et al. therefore call for more research into whether cancer patients exposed to these drugs could transmit these modifications if they have children soon after the end of their treatment. Ultimately, knowing more about how epigenetic changes are involved in inherited diseases may start to provide answers to families affected by cancer.

Abstract Objectives We report four new cases of natural killer–cell enteropathy (NKCE) and similar lymphoproliferative disorders (LPDs), as well as review the literature concerning indolent natural killer (NK)–cell LPDs of the gastrointestinal tract. Methods Pathologic and clinical data were obtained from institutional/referral records. Results Patient 1 (45-year-old man) had anemia; a small intestinal lesion was endoscopically biopsied. Patient 2 (65-year-old woman) had biliary colic, treated with cholecystectomy. Patient 3 (62-year-old man) had a small colonic polyp, biopsied on routine colonoscopy. Patient 4 (68-year-old man) had presumed Crohn disease; multiple biopsies were performed over more than 10 years. Diagnostic specimens showed atypical infiltrates of Epstein-Barr virus–negative lymphocytes with immunophenotypes suggestive of NK cells. In all cases, there was distortion of glandular architecture but no marked intraepithelial lymphocytosis or necrosis. The patients did not receive therapy for lymphoma and were well on follow-up. Conclusions These cases support the indolent nature of NKCE and similar LPDs, and they indicate that involvement outside the alimentary canal may occur.

Background Cutaneous radiation-associated angiosarcoma of the breast (CRAASBr) is a rare complication of radiation therapy (RT) administered for primary breast cancer treatment. Although case series have provided clinical and histological descriptions of this disease, to our knowledge, none have identified trends in presentation and treatments that may contribute to outcomes. Methods Demographic, clinical, histopathologic, and outcomes data for all patients presenting with CRAASBr for treatment or consultation at our institution from 1987 to 2009 were reviewed. Results We identified 33 patients (median age at CRAASBr presentation 71.3 years, range 43.1–87.2 years; median latency period 73.5 months, range 39.6–148.5 months). The most common presentation was breast skin ecchymosis (55 %). In four patients, initial biopsy demonstrated atypical vascular lesions suspicious for, but not diagnostic of, angiosarcoma. All patients underwent mastectomy. Median local recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS) rates were 18.2, 13.0, and 48.5 months, respectively. Patients who underwent resection of all irradiated breast skin as part of the mastectomy trended toward a better median LRFS (80.8 vs. 10.0 months, p  = 0.065), RFS (72.6 vs. 10.0 months, p  = 0.098), and OS (not achieved vs. 29.0 months, p  = 0.054). Conclusions CRAASBr is a potentially devastating consequence of RT for breast cancer, with poor LRFS, RFS, and OS rates. Patients with ecchymotic skin lesions require biopsy. Atypical vascular lesions require careful evaluation to rule out CRAASBr. If the diagnosis is confirmed, radical surgery encompassing both the breast parenchyma and the at-risk radiated skin should be performed.

Detection of the integrin subunit CD103 is a useful diagnostic tool in the diagnosis of hairy cell leukemia (HCL). Currently, flow cytometric analysis (FC) and frozen section immunohistochemistry (IHC) represent the only available methods of detection. This study is the first to describe the successful use of a CD103 antibody to identify HCL and HCL-variant in paraffin sections of formalin- or Bouin solution- fixed specimens (n = 68) using an immunoperoxidase technique. In other B-cell lymphoproliferative disorders that morphologically may resemble HCL, including chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 32), mantle cell lymphoma (n = 23), lymphoplasmacytic lymphoma (n = 27), follicular lymphoma (n = 7), and marginal zone lymphoma (n = 13), lymphoid cells are nonreactive for CD103. In HCL, the CD103 staining pattern is predominantly membranous with delineation of delicate cytoplasmic projections. This CD103 antibody is an extremely valuable addition to the IHC panel for the diagnosis of HCL, especially in cases lacking FC analysis.

Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues 1 – 4 . Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)—an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin 5 . Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2 , the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) arises from clonal (premalignant) haematopoietic precursors in the bone marrow, and BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet radiation.

CXCR4 regulates hematopoietic and tumor cell homing to bone, but its role during osteoclast (OC) development is unknown. We investigated the role of CXCR4 in osteoclastogenesis and in a model of bone metastasis. Compared with controls, mice reconstituted with CXCR4 null hematopoietic cells exhibited elevated markers of bone resorption, increased OC perimeter along bone, and increased bone loss. CXCR4-/- OCs demonstrated accelerated differentiation and enhanced bone resorption in vitro. Furthermore, tumor growth specifically in bone was significantly increased in mice reconstituted with CXCR4-/- hematopoietic cells. Finally, enhancement of bone tumor growth in the absence of CXCR4 was abrogated with the OC inhibitor, zoledronic acid. These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity.

We report four new cases of natural killer-cell enteropathy (NKCE) and similar lymphoproliferative disorders (LPDs), as well as review the literature concerning indolent natural killer (NK)-cell LPDs of the gastrointestinal tract. Pathologic and clinical data were obtained from institutional/referral records. Patient 1 (45-year-old man) had anemia; a small intestinal lesion was endoscopically biopsied. Patient 2 (65-year-old woman) had biliary colic, treated with cholecystectomy. Patient 3 (62-year-old man) had a small colonic polyp, biopsied on routine colonoscopy. Patient 4 (68-year-old man) had presumed Crohn disease; multiple biopsies were performed over more than 10 years. Diagnostic specimens showed atypical infiltrates of Epstein-Barr virus-negative lymphocytes with immunophenotypes suggestive of NK cells. In all cases, there was distortion of glandular architecture but no marked intraepithelial lymphocytosis or necrosis. The patients did not receive therapy for lymphoma and were well on follow-up. These cases support the indolent nature of NKCE and similar LPDs, and they indicate that involvement outside the alimentary canal may occur.

Correspondence to Dr Annette S Kim, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; askim@bwh.harvard.edu Cutaneous involvement by a myeloid neoplasm (myeloid leukaemia cutis), such as chronic myelomonocytic leukaemia (CMML) or acute myeloid leukaemia (AML), can show a spectrum of morphological features and maturation stages, with occasional evidence of histiocytic/dendritic cell differentiation.1 This has to be distinguished from de novo or clonally unrelated histiocytic/dendritic cell neoplasms, which may also arise in patients with underlying myeloid neoplasms. A peripheral blood smear at the time was notable for a marked leucocytosis (white blood cell count 59.68 x 109/L) with 14% monocytes and 25% blasts, normochromic macrocytic anaemia (haemoglobin 9.0 g/dL, mean cell volume (MCV) 102.4 fL) with anisocytosis, and thrombocytopenia with unremarkable morphology (platelets 86 x 109/L). Table 1 Summary of molecular results from skin and bone marrow specimens at various time points (at diagnosis, +3, +7 and +10 months) Gene Variant Variant allele fraction Diagnosis +3 mos +7 mos +10 mos Marrow (%) Marrow (%) Marrow (%) Skin (%) ASXL1 c.2070_2071delTC p.D690fs* 49.60 51.20 41.00 46.00 SRSF2 c.284C>T p.P95L 33.30 26.20 22.90 16.10 NRAS #1 c.37G>T p.G13C 41.70 24.30 26.50 7.80 IDH1 c.394C>T p.R132C 14.00 31.20 FLT3 ITD Present KRAS #1 c.34G>C p.G12R 4.00 5.40 RUNX1 c.736_737insC p.P245fs* 37.20 25.30 11.90 NRAS #2 c.35G>A p.G12D 22.10 21.60 2.20 ETV6 c.459_460insG p.E153fs* 21.00 15.10 KRAS #2 c.182A>G p.Q61R 24.50 Molecular analysis of the skin specimen was very useful in clarifying the diagnosis. In addition to myelomonocytic differentiation, the authors demonstrated that more than half of these lesions can show evidence of dendritic cell differentiation, including mature/blastic plasmacytoid dendritic cells, indeterminate dendritic cells and Langerhans cells.

Greater than 90% of cases of systemic mastocytosis (SM) harbor pathogenic KIT mutations, particularly KIT D816V . Prognostically-significant pathogenic KIT mutations also occur in 30–40% of core binding factor-associated acute myeloid leukemia (CBF-AML), but are uncommonly associated with concurrent SM. By comparison, the occurrence of SM in other myeloid neoplasms bearing pathogenic KIT mutations, particularly those with a chronic course, is poorly understood. Review of clinical next-generation sequencing (NGS) performed at our institutions in patients with known or suspected hematologic malignancies over an 8-year period revealed 64 patients with both a pathogenic KIT mutation detected at one or more timepoints and available bone marrow biopsy materials. Patients with KIT D816V -mutated myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or overlap MDS/MPN ( n  = 22) accounted for approximately one-third of our cohort (34%). Comprehensive morphologic and immunophenotypic characterization revealed that nearly all cases ( n  = 20, 91%) exhibited concurrent SM. In contrast, of the 18 patients (28%) with AML and KIT D816V , only eight (44%) showed evidence of SM at any point in their disease course ( p  = 0.0021); of these eight, the AML component was characterized as AML with myelodysplasia-related changes (AML-MRC) in all but one instance ( n  = 7, 87%). Twelve patients (19%) had pathogenic KIT mutations other than p.D816V, all in the setting of AML (CFB-AML, n  = 7; AML, not otherwise specified, n  = 2; AML-MRC, n  = 1; acute promyelocytic leukemia, n  = 1); only two of these patients (17%), both with CBF-AML, exhibited concurrent SM. The remaining 12 patients (19%) had SM without evidence of an associated hematological neoplasm (AHN). For nearly one-third of the 30 SM-AHN patients in our cohort ( n  = 9, 30%), the SM component of their disease was not initially clinicopathologically recognized. We propose that identification of the KIT D816V mutation in patients diagnosed with MDS, MPN, MDS/MPN, or AML-MRC should trigger reflex testing for SM.