Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event

Jawhar, M., Schwaab, J., Schnittger, S., Sotlar, K., Horny, H.-P., Metzgeroth, G., Müller, N., Schneider, S., Naumann, N., Walz, C., Haferlach, T., Valent, P., Hofmann, W.-K., Cross, N.C.P., Fabarius, A. and Reiter, A. (2015) Molecular profiling of myeloid progenitor cells in multi-mutated advanced systemic mastocytosis identifies KIT D816V as a distinct and late event. Leukemia, 29 (5), 1115-1122. (doi:10.1038/leu.2015.4).

Abstract

To explore the molecular profile and its prognostic implication in systemic mastocytosis (SM), we analyzed the mutation status of granulocyte-macrophage colony-forming progenitor cells (CFU-GM) in patients with KIT D816V+ indolent systemic mastocytosis (ISM, n=4), smoldering SM (SSM, n=2), aggressive SM (ASM, n=1), SM with associated clonal hematologic non-mast cell lineage disorder (SM-AHNMD, n=5) and ASM-AHNMD (n=7). All patients with (A)SM-AHNMD (n=12) carried 1 to 4 (median 3) additional mutations in 11 genes tested, most frequently TET2, SRSF2, ASXL1, CBL and EZH2. In multi-mutated (A)SM-AHNMD, KIT D816V positive single-cell-derived CFU-GM colonies were identified in 8/12 patients (median 60%, range 0–95). Additional mutations were identified in CFU-GM colonies in all patients, and logical hierarchy analysis indicated that mutations in TET2, SRSF2 and ASXL1 preceded KIT D816V. In ISM/SSM, no additional mutations were detected and CFU-GM colonies were exclusively KIT D816V negative. These data indicate that (a) (A)SM-AHNMD is a multi-mutated neoplasm, (b) mutations in TET2, SRSF2 or ASXL1 precede KIT D816V in ASM-AHNMD, (c) KIT D816V is thus a phenotype-modifier towards SM and (d) KIT D816V or other mutations are rare in CFU-GM colonies of ISM/SSM patients which might explain at least in part their better prognosis.

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Contributors

Author: N.C.P. Cross

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