1. MicroRNA changes in chronic lymphocytic leukemia (CLL). As a followup to our work that was published in Leukemia this year on miRNA changes in CLL in response to Ibrutinib treatment, we continued analysis of miRNA profiles in CLL patient cells in relationship to differing prognostic subgroups based on IGHV mutation status, immunophenotypic profile, cytogentic abnormalities, and ZAP-70 positivity; and to circulating B-cells from controls. All of the miRNAs in our panel were significantly differentially expressed in CLL in comparison to controls. Significantly altered miRNA expression was associated with disease stratification based on IgHV mutational status (mutated vs. unmutated) and ZAP-70 positivity. The findings provide evidence that miRNA expression patterns are linked to disease biology and related to diagnosis, prognosis and risk assessment in CLL. A manuscript with the findings is in preparation. 2. RAS-associated Autoimmune Leukoproliferative Disorder (RALD) is a chronic indolent condition that typically presents in childhood with monocytosis, lymphocytosis, autoimmune phenomena, splenomegaly, and variable lymphadenopathy. RALD is characterized by somatic mutations in KRAS or NRAS in hematopoietic cells. Despite the indolent course of RALD, it shares some overlapping clinical features and similar genetic defects with Juvenile Myelomonocytic Leukemia (JMML), which is also characterized by underlying RAS-pathway mutations. The nature of RALD is somewhat controversial as many pediatric hematologist/oncologists argue that RALD may represent a form of JMML or a precursor disease with the potential of transforming into JMML; although malignant transformation to JMML or acute leukemia has not been observed in the large RALD cohort followed at NIH to date. In 2016-2017, in collaboration with Dr. Koneti Rao, we performed whole exome sequencing on peripheral blood mononuclear cells from a cohort of RALD patients. WES identified the known somatic NRAS or KRAS mutations but no other pathogenic mutations (including those commonly seen in JMML) were identified in any of the RALD patients under the age of 40. Variants predicted to be pathogenic were identified in two patients diagnosed with RALD who are over the age of 40, and this is being further investigated. RNA seq was also performed on RALD samples and compared with controls revealing significant differences based on gene ontology analyses, involving multiple cellular processes including immune response and intracellular signaling. One of the RALD patients over the age of 50 has developed two separate B-cell lymphomas. WES of the second diffuse large B-cell lymphoma sample was performed in the past year and showed presence of the persistent somatic NRAS mutation with an additional variant, predicted to be pathogenic, in a known tumor suppressor gene associated with lymphomagenesis. These findings raise the possibility of predisposition to lymphoid neoplasia, but require further study and longterm followup with the RALD cohort; no other RALD patient in our cohort has developed lymphoma. A platform presentation of this research was presented at the International JMML Foundation workshop at the American Society of Hematology Annual meeting in December 2016, and a manuscript is in preparation. 3. MicroRNA profiling of GATA2 deficiency associated myelodysplasia (MDS) / acute myeloid leukemia (AML). Somatic and inherited germline mutations in GATA2 have been identified in patients diagnosed with monocytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. disseminated MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. We previously identified significantly altered levels of miRNAs in EBV transformed cell lines from patients with GATA2 deficiency, and performed functional studies to identify mRNA targets of miR-181c and mir-424. During the past year we expanded functional studies using luciferase reporter constructs furether validating the regulation of MCL-1 by miR-181c, and the regulation of FLT3 and FLT3LG by mir-424. We also completed a collaborative study with Dr. Cynthia Dunbar and Dr. Steven Holland focused on NK-cell lymphopoiesis in GATA2 deficiency. Additionally, we began isolating megakaryocytes from GATA2 patients for transcriptomic analysis, and targetted sequencing. A manuscript was published in Blood with our contribution to the NK-cell GATA2 study, and a final manuscript of the miRNA functional studies is in preparation. 4. Immunophenotypic and morphologic analyses of rare diseases with bone marrow and peripheral blood pathology. Multiple collaborative research studies continued in 2016-2017: a) we characterized abnormal bone marrow hematopoiesis in ADA2 deficiency (or DADA) in collaboration with Dr. Daniel Kastner and Dr. Chip Chambers at Vanderbilt University, a platform presentation for this work was given at the 1st International DADA2 meeting in November 2016; b) ongoing collaborative studies in aplastic anemia with Dr. Neal Young and Dr. Danielle Townsley demonstrated that the drug eltrombopag restores trilineage hematopoiesis and expansion of CD34 positive stem cells in the bone marrow this work was published in the NEJM in 2017, c) in collaboration with Dr. Gulbu Uzel and Steve Holland we characterized abnormal bone marrow features of patients with germline mutations in PIK3CD, and CTLA4 which often present with features overlapping with aplastic anemia and LGL leukemia, and d) continuation of studies in myeloma with Dr. Ola Landgren and Dr. Maryalice Stetler-Stevenson resulted in several publications.

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Bogaert, Delfien J; Kuehn, Hye Sun; Bonroy, Carolien et al. (2018) A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B-cell maturation defects. J Allergy Clin Immunol 141:432-435.e7
Giannelou, Angeliki; Wang, Hongying; Zhou, Qing et al. (2018) Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis 77:612-619
Ahn, Inhye E; Farooqui, Mohammed Z H; Tian, Xin et al. (2018) Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study. Blood 131:2357-2366
Sanchez, Gina A Montealegre; Reinhardt, Adam; Ramsey, Suzanne et al. (2018) JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest 128:3041-3052
Dulau-Florea, Alina E; Young, Neal S; Maric, Irina et al. (2018) Bone Marrow as a Source of Cells for Paroxysmal Nocturnal Hemoglobinuria Detection. Am J Clin Pathol :
McReynolds, Lisa J; Calvo, Katherine R; Holland, Steven M (2018) Germline GATA2 Mutation and Bone Marrow Failure. Hematol Oncol Clin North Am 32:713-728
Parta, Mark; Shah, Nirali N; Baird, Kristin et al. (2018) Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen. Biol Blood Marrow Transplant 24:1250-1259
Boutboul, David; Kuehn, Hye Sun; Van de Wyngaert, ZoƩ et al. (2018) Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 128:3071-3087
Kim, Miriam Y; Yu, Kyung-Rok; Kenderian, Saad S et al. (2018) Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia. Cell 173:1439-1453.e19
Salem, Dalia Abdel-Raouf; Korde, Neha; Venzon, David J et al. (2018) Expression of the IL-6 receptor alpha-chain (CD126) in normal and abnormal plasma cells in monoclonal gammopathy of undetermined significance and smoldering myeloma. Leuk Lymphoma 59:178-186

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