Blood Res.  2016 Mar;51(1):17-22. 10.5045/br.2016.51.1.17.

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

• Youk J
• Koh Y
• Kim JW
• Kim DY
• Park H
• Jung WJ
• Ahn KS
• Yun H
• Park I
• Sun CH
• Lee S
• Yoon SS

• KMID: 2172740
• DOI: http://doi.org/10.5045/br.2016.51.1.17

Abstract

BACKGROUND
Mast 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.
METHODS
First, 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.
RESULTS
WES 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.
CONCLUSION
We 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.

Keyword

Leukemia; Mast cell; C-kit; Individualized medicine

MeSH Terms

Bone Marrow
Diagnosis
DNA
Exome
Humans
Precision Medicine
Induction Chemotherapy
Leukemia
Leukemia, Mast-Cell*
Mast Cells*
Mastocytosis, Systemic
Rare Diseases
RNA
Saliva
Transcriptome
Tretinoin
Up-Regulation
Dasatinib
DNA
RNA
Tretinoin

Figure

• 

  Fig. 1 Circus plot of structural variations, copy number variations, single nucleotide variations, and differentially expressed genes for mast cell leukemia. From the inner to outer track, this plot includes interchromosomal and intrachromosomal fusion genes (blue and orange), copy number variations (centripetal red line for loss, centrifugal red line for gain), genotype of single nucleotide variations, remarkably expressed genes (red line, RPKM ≥25), gene names, and chromosomal numbers. Chromosomes without mutations are not shown.

Reference

1. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013; 121:1285–1295. PMID: 23243287.

2. Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32:3264–3274. PMID: 25154823.

3. Valent P, Sotlar K, Sperr WR, et al. Refined diagnostic criteria an classification of mast cell leukemia (MCL) and myelomastocytieukemia (MML): a consensus proposal. Ann Oncol. 2014; 25:1691–1700. PMID: 24675021.

4. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25:1754–1760. PMID: 19451168.

5. McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20:1297–1303. PMID: 20644199.

6. Cibulskis K, Lawrence MS, Carter SL, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013; 31:213–219. PMID: 23396013.

7. Li J, Lupat R, Amarasinghe KC, et al. CONTRA: copy number analysis for targeted resequencing. Bioinformatics. 2012; 28:1307–1313. PMID: 22474122.

8. Li H, Handsaker B, Wysoker A, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25:2078–2079. PMID: 19505943.

9. Ge H, Liu K, Juan T, Fang F, Newman M, Hoeck W. FusionMap: detecting fusion genes from next-generation sequencing data at base-pair resolution. Bioinformatics. 2011; 27:1922–1928. PMID: 21593131.

10. Spector MS, Iossifov I, Kritharis A, et al. Mast-cell leukemia exome sequencing reveals a mutation in the IgE mast-cell receptor β chain and KIT V654A. Leukemia. 2012; 26:1422–1425. PMID: 22173243.

11. Akin C, Metcalfe DD. Systemic mastocytosis. Annu Rev Med. 2004; 55:419–432. PMID: 14746529.

12. Georgin-Lavialle S, Aguilar C, Guieze R, et al. Mast cell sarcoma: a rare and aggressive entity-report of two cases and review of the literature. J Clin Oncol. 2013; 31:e90–e97. PMID: 23129735.

13. Mital A, Piskorz A, Lewandowski K, Wasąg B, Limon J, Hellmann A. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib. Eur J Haematol. 2011; 86:531–535. PMID: 21362052.

14. Georgin-Lavialle S, Lhermitte L, Suarez F, et al. Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor. Eur J Haematol. 2012; 89:47–52. PMID: 22324351.

15. Valent P, Berger J, Cerny-Reiterer S, et al. Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann Hematol. 2015; 94:223–231. PMID: 25209843.

16. Soucie E, Hanssens K, Mercher T, et al. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood. 2012; 120:4846–4849. PMID: 23074272.

17. Valentini CG, Rondoni M, Pogliani EM, et al. Mast cell leukemia: a report of ten cases. Ann Hematol. 2008; 87:505–508. PMID: 18172645.

18. Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012; 92:1619–1649. PMID: 23073628.

19. Gotlib J, Berubé C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005; 106:2865–2870. PMID: 15972446.

20. Growney JD, Clark JJ, Adelsperger J, et al. Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. Blood. 2005; 106:721–724. PMID: 15790786.

21. Quintas-Cardama A, Aribi A, Cortes J, Giles FJ, Kantarjian H, Verstovsek S. Novel approaches in the treatment of systemic mastocytosis. Cancer. 2006; 107:1429–1439. PMID: 16948123.

22. Lee S, Lee H, Kim J, et al. Development and biological evaluation of potent and selective c-KIT(D816V) inhibitors. J Med Chem. 2014; 57:6428–6443. PMID: 25004409.

23. Kim DY, Joo YD, Lim SN, et al. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015; 126:746–756. PMID: 26065651.