Clinico-Pathological Characteristics of RAS Associated Autoimmune Lymphoproliferative Syndrome Like Disease (RALD), and RAS Mutated Juvenile Myelomonocytic Leukemia (JMML)

Abstract 5169

Autoimmune lympho proliferative syndrome (ALPS) is a disease characterized by dysfunction of the FAS-mediated apoptotic pathway, currently categorized as Type Ia, germline TNFRSF6/FAS mutation; Type Ib, germline FAS ligand mutation; Type Is, somatic TNFRSF6/FAS mutation; and Type II, germline Caspase 10 mutation. Patients exhibit lymphadenopathy, hepatosplenomegaly, and autoimmune diseases such as immune cytopenia and hyper-γ-globulinemia. An additional subclassification has been proposed that includes Types III, which has been defined as that with no known mutation but with a defect in FAS-mediated apoptosis. Juvenile myelomonocytic leukemia (JMML) is a chronic leukemia in children. Patients show lymphadenopathy, hepatosplenomegaly, leukocytosis associated with monocytosis, anemia, thrombocytopenia. About 80% of patients with JMML have been shown to have a genetic abnormality in their leukemia cells including mutations of NF1, RAS family, CBL, or PTPN11. HSCT is currently considered the only curative treatment. However, some patients have been shown to achieve remission without HSCT. Interestingly, there are several cases of JMML reported simultaneously having clinical and laboratory findings compatible with autoimmune disease. Germline RAS pathway mutations cause Costello (HRAS), Noonan (PTPN11, KRAS, and SOS1), and cardio-facio-cutaneous (CFC) syndromes (KRAS, BRAF, MEK1, and MEK2). Patients with Costello and Noonan syndromes have an increased propensity to develop solid and hematopoietic tumors, respectively.

We have recently reported a unique disease which lies between ALPS and JMML. The patients were characterized by prominent autoimmune cytopenia, lymphoadenopathy/splenomegaly and moderate monocytosis resembling to ALPS and JMML, but they did not satisfy the diagnostic criteria for ALPS or JMML. KRAS mutation in hemopoietic precursors including T and myeloid linage is the common molecular feature, and we have recently proposed these cases to be defined under a new disease entity of RAS associated ALPS like disease (RALD). These patients were characterized by activated T cells resistant to IL-2 depletion but not to FAS-dependent apoptosis associated with the decreased expression of pro-apoptotic protein BIM.

Since somatic RAS mutation has been identified in classical JMML and RALD, it is tempting to speculate that the developmental stage dependent RAS mutation of hemopoietic stem/precursors may determine the clinical features of JMML and RALD. Clinico-pathological characteristics of three RALD cases and three JMML cases cured without SCT will be presented and discussed.