Blood Spotlight JMML and RALD (Ras-associated autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities

Ras-associated autoimmune leukoproliferative disorder (RALD) is a nonmalignant clinical syndrome initially identified in a subset of putative autoimmune lymphoproliferative syndrome (ALPS) patients. Similar to patients with ALPS, RALD patients present with lymphadenopathy,massive splenomegaly, increasedcirculatingBcells, hypergammaglobulinemia, and autoimmunity. In contrast to ALPS, biomarkers such as CD4/CD8 double negative T-cell receptor ab (TCRab) T cells and serum vitamin B12 levels are not always increased, and germline or somatic mutations in FAS, FASL, or CASP10 are absent in RALD. Persistent absolute or relative monocytosis is a cardinal feature of RALD. Bone marrow and peripheral blood smear findings overlap with those of juvenile myelomonocytic leukemia (JMML) in children or chronic myelomonocytic leukemia (CMML) in older patients. Activating somatic mutations that cause amino acid substitutions that affect codons 12 or 13 in KRAS or NRAS were identified in myeloid and lymphoid lineages. In 2009, the revised classification and nomenclature of RALD was adopted to distinguish it from ALPS. JMML is an aggressive malignant hematopoietic neoplasm of childhood with myelodysplastic and myeloproliferative features. Patients present with splenomegaly, fever, thrombocytopenia, monocytosis, and excess myelomonocytic cells that infiltrate skin and vital organs. JMML accounts for 20% to 30% of myelodysplastic/ myeloproliferative disorders in thepediatric population.Theprognosis for JMML is poor withmedian survival of 1 year for untreated patients. Hematopoietic stem cell transplantation has become the standard of care for JMML. CMML has a variable course in adults and often requires chemotherapy.