Vinodh Pillai

Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma.

Washington, District of Columbia; Hematology Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; Phoenicia Biosciences, Weston, Massachusetts Conflict of interest: S. Perrine: Inventor on patents related to this work. Contract grant sponsor: NIH; Contract grant numbers: 1P50 HL-118006, R01 DK-52962, R41 HL-108516, R42 HL-110727. *Correspondence to: Susan Perrine, MD, Hemoglobinopathy Thalassemia Research Unit, Boston University School of Medicine, 72 East Concord Street, L909, Boston, MA 02118. E-mail: sperrine@bu.edu Received for publication: 27 September 2016; Revised: 13 October 2016; Accepted: 17 October 2016 Published online: 20 October 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ajh.24590

TAFRO syndrome or Castleman-Kojima syndrome: a variant of multicentric Castleman disease

![Figure][1] A 14-year-old white young man was transferred from an outside hospital with a 4-week history of fever, 30-lb weight gain, and diarrhea. He was noted to have anasarca, elevated C-reactive protein (CRP), elevated creatinine, anemia, and thrombocytopenia. A detailed clinical work-up

Mature T‐ and NK‐cell non‐Hodgkin lymphoma in children and young adolescents

Mature T/Natural killer (NK)‐cell neoplasms of children and the young adolescent population exhibit higher prevalence in Central and South American and Asian populations and many are associated with Epstein‐Barr virus (EBV). They are represented in large part by extranodal T/NK cell lymphomas‐ nasal‐type or extra nasal‐type, chronic lymphoproliferative disorders of T/NK cells or chronic active EBV disease, systemic EBV‐positive lymphoproliferative disorders of childhood, hydroa vacciniforme‐like lymphoma, hepatosplenic T‐cell lymphoma and primary cutaneous gamma/delta T‐cell lymphoma among others. Many T/NK cell neoplasms in this age group are derived from cells of the innate immune system, in contrast to adults where they are predominantly from the adaptive immune system. The genetic basis of T/NK cell lymphomas in children and young adolescents remains largely unknown. Anthracycline‐based regimens and haematopoietic stem cell transplants (allogeneic and autologous) are current treatment modalities, however it is anticipated that novel targeted therapeutic agents will be available in the near future.

CBL family E3 ubiquitin ligases control JAK2 ubiquitination and stability in hematopoietic stem cells and myeloid malignancies

Janus kinase 2 (JAK2) is a central kinase in hematopoietic stem/progenitor cells (HSPCs), and its uncontrolled activation is a prominent oncogenic driver of hematopoietic neoplasms. However, molecular mechanisms underlying the regulation of JAK2 have remained elusive. Here we report that the Casitas B-cell lymphoma (CBL) family E3 ubiquitin ligases down-regulate JAK2 stability and signaling via the adaptor protein LNK/SH2B3. We demonstrated that depletion of CBL/CBL-B or LNK abrogated JAK2 ubiquitination, extended JAK2 half-life, and enhanced JAK2 signaling and cell growth in human cell lines as well as primary murine HSPCs. Built on these findings, we showed that JAK inhibitor (JAKi) significantly reduced aberrant HSPCs and mitigated leukemia development in a mouse model of aggressive myeloid leukemia driven by loss of Cbl and Cbl-b Importantly, primary human CBL mutated (CBLmut ) leukemias exhibited increased JAK2 protein levels and signaling and were hypersensitive to JAKi. Loss-of-function mutations in CBL E3 ubiquitin ligases are found in a wide range of myeloid malignancies, which are diseases without effective treatment options. Hence, our studies reveal a novel signaling axis that regulates JAK2 in normal and malignant HSPCs and suggest new therapeutic strategies for treating CBLmut myeloid malignancies.

Flow Cytometry in Pediatric Hematopoietic Malignancies

Utility of flow cytometry in the evaluation of pediatric hematopoietic neoplasms and the differences from adult hematopoietic neoplasms are discussed in this review. Distinction of hematogones from B-lymphoblasts, detection of residual/relapsed disease after novel targeted therapies, and evaluation of pediatric myeloid neoplasms are discussed.

Heterogeneity of surface CD19 and CD22 expression in B lymphoblastic leukemia

No abstract is available for this article. This article is protected by copyright. All rights reserved.

Aberrant splicing in B-cell acute lymphoblastic leukemia

Abstract Aberrant splicing is a hallmark of leukemias with mutations in splicing factor (SF)-encoding genes. Here we investigated its prevalence in pediatric B-cell acute lymphoblastic leukemias (B-ALL), where SFs are not mutated. By comparing these samples to normal pro-B cells, we found thousands of aberrant local splice variations (LSVs) per sample, with 279 LSVs in 241 genes present in every comparison. These genes were enriched in RNA processing pathways and encoded ∼100 SFs, e.g. hnRNPA1. HNRNPA1 3′UTR was most pervasively mis-spliced, yielding the transcript subject to nonsense-mediated decay. To mimic this event, we knocked it down in B-lymphoblastoid cells and identified 213 hnRNPA1-regulated exon usage events comprising the hnRNPA1 splicing signature in pediatric leukemia. Some of its elements were LSVs in DICER1 and NT5C2, known cancer drivers. We searched for LSVs in other leukemia and lymphoma drivers and discovered 81 LSVs in 41 additional genes. Seventy-seven LSVs out of 81 were confirmed using two large independent B-ALL RNA-seq datasets, and the twenty most common B-ALL drivers, including NT5C2, showed higher prevalence of aberrant splicing than of somatic mutations. Thus, post-transcriptional deregulation of SF can drive widespread changes in B-ALL splicing and likely contributes to disease pathogenesis.

Severe Mucha-Habermann-Like Ulceronecrotic Skin Disease in T-Cell Acute Lymphoblastic Leukemia Responsive to Basiliximab and Stem Cell Transplant

A 5‐year‐old girl with T‐cell acute lymphoblastic leukemia (T‐ALL) developed a progressive eruption of crusted papules and ulcerative plaques involving 80% of her body surface area with histopathology consistent with febrile ulceronecrotic Mucha–Habermann disease (FUMHD), although multiple specimens also contained clonal leukemic cells. Her skin disease was refractory to many classic treatments for FUMHD, including methotrexate, and became so severe that concern about superinfection prevented intensification of chemotherapy for her malignancy. The addition of basiliximab promoted gradual improvement of the skin, allowing for chemotherapy intensification and subsequent bone marrow transplantation, after which the eruption resolved completely. This report describes a severe case of FUMHD‐like eruption associated with clonal leukemic cells that improved with basiliximab, suggesting anti‐CD25 therapy as a novel treatment for ulceronecrotic skin disease in the setting of high interleukin‐2 levels.

A case report of Pediatric Brucellosis in an Algerian immigrant

Abstract An 8-year old girl presented to our facility with a 10-day history of fever, fatigue, abdominal pain and refusal to walk. She recently travelled from her native Algeria where she first developed symptoms. On evaluation, she was ill-appearing, febrile and tachycardic with hepatosplenomegaly and lymphadenopathy noted on examination. A strong musty odor was also noted from the child. Laboratory evaluation revealed pancytopenia, hyponatremia, and an elevated AST, ALT, and LDH. Malaria testing was negative, as was a PPD. On further questioning, the family reported multiple sick contacts in Algeria with similar symptoms. After discussion with Oncology and Infectious Diseases, she underwent a bone marrow biopsy that was significant for multiple non-caseating ring granulomas. She was started on combination therapy of doxycycline and for presumed brucellosis infection with improvement in her symptoms and resolution of fever. Bone marrow culture returned several days later positive for Brucella melitensis.

Marked eosinophilia masking B lymphoblastic leukemia

A 13-year-old male presented with progressive shortness of breath and cough. A CBC showed leukocytosis (WBC 133850/ll, hemoglobin 7.8 g/dl, hematocrit 25.8%, platelet 532000/ll) with marked eosinophilia (eosinophils 71%, segmented neutrophils 15%, bands 4%, basophils 4%, monocytes 1%, lymphocytes 3% with absolute eosinophil count of 95170/ll). Radiological studies showed cardiomegaly and bilateral pleural effusions consistent with restrictive cardiomyopathy. A workup for infectious and autoimmune causes of eosinophilia were negative. Bone marrow aspirate was spicular and hypercellular with atypical hyperlobated eosinophils. Bone marrow biopsy showed that the majority of the cellularity was composed of atypical eosinophils (upper panel, middle). Flow cytometric studies were negative for an abnormal blast population. Conventional cytogenetics revealed a normal karyotype, FISH studies were negative for PDGFRA, PDGFRB, FGFR1, BCR-ABL1 or CBFB-MYH11 translocations, and comparative genomic hybridization studies were unremarkable. Molecular studies for PDGFRA, MPL W515, MPL S505, JAK2 V617F, JAK2 Exon 12, and JAK2 Exon 13 mutations were negative. With a presumptive diagnosis of hypereosinophilic syndrome, he was treated with prednisone, hydroxyurea and imatinib for 2 months. There was a decrease in WBC but not resolution of his eosinophilia or his cardiac symptoms. On review of bone marrow biopsies at our institution, dense paratrabecular aggregates composed of small lymphoid cells (upper panel, middle, and right) were noted that were positive for CD19, CD34, and TdT (lower panel, left, and middle) consistent with lymphoblasts. Though the overall blast count was less than 25%, focally, the blast count was very high, consistent with a diagnosis of B-lymphoblastic leukemia (B-LL). A repeat bone marrow biopsy performed to confirm the diagnosis revealed small lymphoid blasts that constituted 11% of the cellularity in the aspirate (lower panel, right) and approximately 50% in the biopsy (not shown). Flow cytometric studies showed an abnormal blast population that was CD45(dim), CD10(bright), CD19, CD34, CD38(dim), and TdT. Routine karyotype, FISH, and genome wide single