Research accomplishments of this project include: 1) This project allows us to study the largest cohort of patients with ALPS, one of the first genetic disorders of immunedysregulation. ALPS natural history study based on follow up of these patients over 20 yeas has been completed and a manuscript summarizing the critical features of the clinical and molecular pathogenesis in 150 patients with ALPS-FAS with a median followup of 13 years has been published as a plenary paper in an eminent hematological journal this year (Blood. 2014 Mar 27;123(13):1989-99). This included the validation of novel biomarkers of disease activity such as increased serum Vitamin B12 levels as well as establishing new modes of treatment for the disorder. Study of ALPS has elucidated the role of fas mediated apoptosis in lymphocyte homeostasis and lymphoma genesis. 2)This project has also led to identifying new genetic causes of ALPS like disorders by identification of mutations affecting RAS pathway in 14 patients, otherwise known as Ras Associated Leukoproliferative Disorder (RALD) : RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic young patients. (Blood 2015 Apr 30;125(18):2753-8). 3) Provided below is the current classification scheme that we have devised for ALPS patients based on the particular molecular defect present: ALPS-FAS : mutations in the TNFRSF6 (tumor necrosis factor receptor superfamily 6) gene, encodes the protein CD95 (Fas). ALPS-sFas: somatic mutant: TNFRSF6 gene defect in the double negative T (DNT) cell population. ALPS-FASLG: mutations in TNFSF6 gene, encodes the protein CD95 ligand (Fas ligand). ALPS-CASP10: mutations in CASP10 gene, encodes caspase-10. ALPS-U: associated mutation unidentified to date. 4) With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <www.ncbi.nlm.nih.gov/lovd/home.php?select_db=FAS>. We are also continuing our efforts to streamline the techniques of apoptosis assay by evaluating Fas mediated cell death and cell survival with serum starvation in lymphocyte and monocyte subsets so that these test procedures can be readily adapted in more clinical laboratories for patient evaluation in ALPS and RALD respectively. 5) Extended the use of PET scans as an imaging modality in patients with ALPS associated lymphadenopathy as a tool to monitor patients with suspected ALPS associated cancer of the lymphoid system (lymphoma). We have identified lymphomas associated with ALPS-FAS in approximately 10% of our patients. Ongoing critical surveillance for lymphoma and its early diagnosis and treatment has been pursued over the last 20 years of longitudinal follow up of these patients. 7) Continued search for new genetic mutations in the subgroup of patients with ALPS and undetermined genetic defects using emerging genomic and cell biology tools. Currently a large group of patients with unknown molecular etiologies are being subjected to whole exome DNA sequencing and analysis. Some novel immunedysregulatory syndromes are identified leading to validation of novel candidate genes and publication listed below over the last 2 years.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code
Comrie, William A; Faruqi, Aiman J; Price, Susan et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.e8
Buchbinder, David; Seppanen, Mikko; Rao, V Koneti et al. (2018) Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes. J Pediatr Hematol Oncol 40:e319-e322
Ucar, Didar; Kim, Jane S; Bishop, Rachel J et al. (2017) Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). Ocul Immunol Inflamm 25:703-709
Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61
Rao, V Koneti; Webster, Sharon; Dalm, Virgil A S H et al. (2017) Effective ""activated PI3K? syndrome""-targeted therapy with the PI3K? inhibitor leniolisib. Blood 130:2307-2316
Dulau Florea, Alina E; Braylan, Raul C; Schafernak, Kristian T et al. (2017) Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol 139:1032-1035.e6
Xie, Yi; Pittaluga, Stefania; Price, Susan et al. (2017) Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica 102:364-372
Weinreich, Michael Alexander; Vogel, Tiphanie P; Rao, V Koneti et al. (2017) Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. Front Pediatr 5:49
Rao, V Koneti (2016) Serendipity in splendid isolation: rapamycin. Blood 127:5-6
Cruz, Anthony C; Ramaswamy, Madhu; Ouyang, Claudia et al. (2016) Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nat Commun 7:13895

Showing the most recent 10 out of 46 publications