Subject(s)
Hypereosinophilic Syndrome/classification , Hypereosinophilic Syndrome/genetics , Hypereosinophilic Syndrome/mortality , Adult , Aged , Aged, 80 and over , Female , High-Throughput Nucleotide Sequencing/methods , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
CD123 is the α-subunit of the interleukin-3 receptor; it represents a potential therapeutic target in systemic mastocytosis (SM) given its absent expression on normal/reactive mast cells (MCs) and aberrant expression on neoplastic MCs. We studied 58 SM patients to define CD123 expression patterns by immunohistochemistry and its clinical significance. Two hematopathologists independently scored bone marrow slides using predefined histologic parameters. In all, 23 patients had indolent SM (ISM), 10 aggressive SM (ASM), 23 SM with associated hematological neoplasm (SM-AHN) and 2 had mast cell leukemia (MCL). MC_CD123 expression was demonstrable in 37 (64%) cases; expression rates were 100%, 61%, 57% and 0% in ASM, ISM, SM-AHN and MCL, respectively (P=0.02). Focal proliferation of plasmacytoid dendritic cells (PDCs) around MC aggregates, suggesting a tumor-promoting role for PDCs, was noted in 44 (76%) cases, and was significantly higher in CD123-positive versus -negative cases (87% versus 50%, P=0.005). CD123 expression and its staining intensity had prognostic value in SM-chronic myelomonocytic leukemia and nonindolent SM patients, respectively. These observations suggest that targeting CD123 in SM may have direct (via MCs) and indirect (via PDCs) antitumor effects and clinical trials to that effect require laboratory correlative studies to address the observed target expression heterogeneity.
Subject(s)
Biomarkers, Tumor/metabolism , Hematologic Neoplasms/metabolism , Interleukin-3 Receptor alpha Subunit/metabolism , Leukemia, Mast-Cell/metabolism , Mastocytosis, Systemic/metabolism , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hematologic Neoplasms/pathology , Humans , Immunoenzyme Techniques , Leukemia, Mast-Cell/pathology , Male , Mastocytosis, Systemic/pathology , Middle Aged , Neoplasm Staging , Prognosis , Retrospective StudiesSubject(s)
Bone Marrow/pathology , Interleukin-3 Receptor alpha Subunit/metabolism , Mast Cells/pathology , Mastocytosis, Systemic/pathology , Bone Marrow/metabolism , Flow Cytometry , Humans , Immunoenzyme Techniques , Immunophenotyping , Mast Cells/metabolism , Mastocytosis, Systemic/metabolism , Tumor Cells, CulturedABSTRACT
Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.
