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Clonal evolution and heterogeneity in advanced systemic mastocytosis revealed by single-cell DNA sequencing

Lim KH, Wu JN, Huang TY, Jhuang JY, Chang YC, Lin HC, Chiang YH, Su YW, Chen CG, Chang YF, Lin J.
Blood Advances Mar 2021

Advanced systemic mastocytosis (advSM) is a clonal stem cell neoplasm that includes aggressive SM (ASM), SM with an associated hematologic neoplasm (AHN), and mast cell leukemia.1-3 The median survival is 41 months for ASM, 24 months for SM-AHN, and <6 to 18 months for mast cell leukemia.4-6 KIT D816V mutation can be detected in >90% of SM patients.7 Interestingly, multilineage involvement of KIT D816V and multimutations in other genes such as SRSF2, ASXL1, and RUNX1 are frequently detected in advSM.8 Some of the above-mentioned mutations were found to precede the KIT D816V mutation, indicating that the KIT mutation is a phenotypic mutation in SM.9 The presence and number of several mutated genes such as the SRSF2-ASXL1-RUNX1 panel are associated with worse prognosis in advSM.10-12 Recently, the multikinase inhibitor midostaurin was approved for the treatment of advSM on the basis of its clinical activity in 116 adults with advSM.13 Currently, both primary and acquired resistance to midostaurin are clinical challenges in advSM. The complexity and dynamics of mutational profiles in midostaurin-treated advSM have been studied by using serial next-generation sequencing, and acquisition of additional mutations or increasing variant allele frequency (VAF) in KRAS/NRAS, RUNX1, IDH2, or NPM1 were associated with progression.14 However, the changes in clonal architecture under the selection pressure of midostaurin in advSM are still elusive. In contrast to traditional bulk DNA sequencing (DNA-seq), genomic analysis at single-cell resolution may provide a better opportunity to resolve clonal architecture in advSM. Here, we report the clonal evolution and heterogeneity in a case of ASM associated with chronic myelomonocytic leukemia (CMML) being treated with midostaurin and azacitidine at the single-cell level.




Institution Type


Indication / Modality

Mast Cell Leukemia, Chronic Myelomonocytic Leukemia

Goal of Study

Therapeutic Resistance, Clonal Evolution, Clonal Heterogeneity, Retrospective

Key Genes


PAD Project


Analytes Assessed

SNV, InDels

Sample Storage

Fresh Frozen

Sample Prep

Whole Cells

Sample Type

Patient Material, PBMC

Tissue / Organ

Bone Marrow Aspirates



Panel Used

Catalog AML Panel

Proof Point Demonstrated

Better than Bulk, Phylogeny, Co-occurrence