A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data

Abstract

BackgroundMast cell leukemia (MCL) is the most aggressive form of systemic mastocytosis disorders. Owing to its rarity, neither pathogenesis nor standard treatment is established for this orphan disease. Hence, we tried to treat a patient with MCL based on the exome and transcriptome sequencing results of the patient's own DNA and RNA.MethodsFirst, tumor DNA and RNA were extracted from bone marrow at the time of diagnosis. Germline DNA was extracted from the patient's saliva 45 days after induction chemotherapy and used as a control. Then, we performed whole-exome sequencing (WES) using the DNA and whole transcriptome sequencing (WTS) using the RNA. Single nucleotide variants (SNVs) were called using MuTect and GATK. Samtools, FusionMap, and Gene Set Enrichment Analysis were utilized to analyze WTS results.ResultsWES and WTS results revealed mutation in KIT S476I. Fusion analysis was performed using WTS data, which suggested a possible RARα-B2M fusion. When RNA expression analysis was performed using WTS data, upregulation of PIK3/AKT pathway, downstream of KIT and mTOR, was observed. Based on our WES and WTS results, we first administered all-trans retinoic acid, then dasatinib, and finally, an mTOR inhibitor.ConclusionWe present a case of orphan disease where we used a targeted approach using WES and WTS data of the patient. Even though our treatment was not successful, use of our approach warrants further validation.

Comprehensive Analysis of Acquired Genetic Variants and Their Prognostic Impact in Systemic Mastocytosis

“…In order to elucidate whether any of these mutated genes confers an adverse prognosis, multiple studies have been conducted in SM [11][12][13]29,32,68,80,90,120,160,176], from which a few include medium to large patient cohorts (n ≥ 100) [12,29,32,68,97]. Of note, the number of genes screened in these studies is highly variable, ranging from 9 genes [80] to 410 genes [13], with a few patients being investigated by whole-genome [13] or wholeexome [42,[177][178][179] sequencing. Overall, these studies found a total of 30 different genes to be mutated in SM (Table 2 and Table S1), from which 11 (i.e., ASXL1, CBL, DNMT3A, EZH2, JAK2, KRAS, NRAS, RUNX1, SF3B1, SRSF2, TET2) are recurrently mutated genes in several SM cohorts (Tables 3-5).…”

Mast Cell Tumors

“…Recent approaches such as next-generation sequencing will reveal even minor mutations or single nucleotide polymorphisms in neoplastic mast cells. In fact, Spector et al [30] and Youk et al [31] discovered a human mast cell leukemia-specific mutation in several genes. As the cost of these approaches decreases, they will be introduced in the veterinary field, probably leading to the deep understanding of mast cell tumorigenesis among species.…”

Application of next generation sequencing in the diagnosis and management of mast cell leukemia

“…However, other mutations in SRSF2 , ASXL1 and/or RUNX1 have also been found in the patients with KIT D816V positive systemic mastocytosis, indicating that mutations in more than one gene may be necessary for leukemogenesis [ 5 6 ]. In this issue of the Blood Research , Youk et al [ 7 ] used next generation sequencing (NGS) to find mutations possibly causing the disease in a patient diagnosed with MCL. The whole exome sequencing revealed KIT S476I and whole transcriptome sequencing demonstrated possibly RARα-B2M fusion gene, and the authors used the results in personalized treatment.…”