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317 Germline Gain-of-Function JAK3 Mutation in Familial Chronic Lymphoproliferative Disorder of NK Cells

Program: Oral and Poster Abstracts
Type: Oral
Session: 203. Lymphocytes, Lymphocyte Activation, and Immunodeficiency, including HIV and Other Infections: Hematologic Malignancies and COVID-19
Hematology Disease Topics & Pathways:
autoimmune disorders, Leukemia, Diseases, LGLL, immunodeficiency, Biological Processes, Immune Disorders, Lymphoid Malignancies, genomics, Clinically relevant, Proliferative disorders, hematopoiesis, pathogenesis, signal transduction
Sunday, December 6, 2020: 10:45 AM

Harry Lesmana, MD1,2, Marcela Popescu, MD3*, Sara Lewis, MS, LCGC4*, Sushree Sangita Sahoo, PhD5*, Charnise Goodings-Harris, PhD6, Mihaela Onciu, MD, FACP7, John Kim Choi, MD, FACP7*, Clifford Takemoto, MD1*, Kim E. Nichols, MD8 and Marcin Wlodarski, MD, PhD9

1Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
2Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH
3Department of Pediatrics, East Tennessee State University, Johnson City, TN
4St. Jude Children's Research Hospital, Memphis, TN
5Hematology, St. Jude Children's Research Hospital, Memphis, TN
6St Jude Children's Research Hospital, Memphis, TN
7Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN
8Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN
9Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN

Chronic lymphoproliferative disorder of NK-cells (CLPD-NK) predominantly occurs in adults with a median age of diagnosis at 60 years. It is characterized by a persistent increase (≥2 x 109/L, for > 6 months) of mature NK-cells in peripheral blood with an indolent clinical course similar to T-cell large granular lymphocytic leukemia (T-LGL). Somatic gain-of-function (GOF) mutations in STAT3 have been identified in approximately one-third of patients with CLPD-NK. On the other hand, somatic GOF mutations in JAK3 recurrently occur in various types of T-cell neoplasms and exert a GOF effect, unlike biallelic germline loss-of-function mutations found in severe combined immunodeficiency (Figure 1). Here we report on the discovery of a germline GOF JAK3 mutation as a first germline cause of CLPD-NK. Two individuals from one nonconsanguineous family (mother and son) presented at ages 35 and 12 years old with NK cell lymphoproliferation, lymphadenopathy, splenomegaly and autoimmune symptoms. The mother had history of vasculitis while the son was diagnosed with CVID, recurrent multilineage autoimmune cytopenia and subsequently developed psoriasis at 18 years old. The immunological phenotype was assessed in depth in the son and revealed hypogammaglobulinemia with normal vaccine response, expanded NK cells (between 40-60% of total lymphocytes), decreased FOXP3 expression in regulatory T cells and B cell subsets showing decreased total and isotype-switched memory B cells. Flow cytometry revealed expanded population of aberrant NK cells with normal KIR panel. Marrow studies revealed normal karyotype, cellularity and maturation but prominent large granular lymphocytes with benign cytology.

Genomic studies identified a novel germline heterozygous JAK3 variant (c.1520A>C/p.Q507P) located at the linker between SH2 and pseudokinase domain (Figure 1). No additional somatic mutations were found. The JAK3 variant was not present in gnomAD database but previously reported as somatic mutation in a patient with T cell prolymphocytic leukemia (Bergmann, Genes Chromosomes Cancer 2014) and predicted to exert a GOF effect. It is well known that JAK3 activation promotes STAT signaling, a known key player in lymphoproliferation. To better understand the biological effect in patient cells, we performed pSTAT5 phosphorylation assay in primary blood lymphocytes after IL2 stimulation, revealing increased pSTAT5 phosphorylation in patient’s NK cells. The IL3-dependent BaF3 cell line (containing human wild type JAK3) has been previously used as a robust model to study the effect of JAK3 mutations (Elliott et al. Blood 2011). We therefore introduced the p.Q507P mutation using CRISPR/Cas9 system and used known GOF mutation p.A572V as positive control. While untransduced BaF3 cells died without IL3, p.Q507P-mutant BaF3 cells survived and rapidly expanded without IL3, showing comparable results to positive control. Finally, using western blot we identified constitutive phosphorylation as expected mechanism underlying the lymphoproliferation p.Q507P-mutant cells.

In summary, we identify JAK3 as the first germline cause underlying familial CLPD-NK and describe a novel primary immune dysregulatory disorder characterized by non-malignant NK lymphoproliferation with CVID and autoimmune dysregulation. These findings broaden the genetic spectrum of primary immunodeficiency and immune dysregulatory conditions.

Disclosures: Takemoto: Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: DSMB Aplastic Anemia Trial. Nichols: Incyte corporation: Research Funding.

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