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Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis of SM, subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multi-mutated clones are characteristic of advanced SM, especially SM with