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Review Article
Understanding the Molecular Basis of Juvenile Myelomonocytic Leukemia and Its Application for Novel Drugs Development
Clin Pediatr Hematol Oncol 2018;25:23-30.
Published online April 30, 2018
© 2018 Korean Society of Pediatric Hematology-Oncology and Korean Society for Pediatric Neuro-Oncology

In-sang Jeon, M.D.

Department of Pediatrics, College of Medicine, Gachon University, Incheon, Korea
Correspondence to: In-sang Jeon
Department of Pediatrics, College of Medicine, Gachon University, 21 Namdongdaero 774 beongil, Namdong-gu, Incheon 21565, Korea
Tel: +82-32-460-8382 Fax: +82-32-460-3224 E-mail: isjeon@gilhospital.com
Received March 21, 2018; Revised March 29, 2018; Accepted April 5, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
To date, hematopoietic stem cell transplantation (HSCT) is the only choice of therapy for most patients with juvenile myelomonocytic leukemia (JMML). Relapse remains a major problem. Approximately 90% of patients carry either somatic or germline mutations of genes participating in RAS signal transduction such as PTPN11, CBL, K-RAS, N-RAS, or NF1 in their leukemic cells, allowing an understanding of the molecular pathophysiology of JMLL and the development of novel drugs. As these genetic aberrations are mutually exclusive, the genetic change observed in JMML helps us to establish the diagnosis of JMML. Furthermore, the genetic abnormalities of JMML are an important prognostic factor, as the type of abnormality may determine disease progression. Recent studies have revealed a strong association between hypermethylation of some genes and already known poor prognostic factors such as older age, elevated fetal hemoglobin at diagnosis, and somatic mutation of PTPN11. These molecular characteristics may be the basis for a guideline to determine the treatment, especially when to proceed with HSCT. Recently, novel drugs have been used based on these molecular characteristics. 5-Azacitidine, an inhibitor of DNA methyltransferase and tipifarnib, a selective farnesyl transferase inhibitor, have been used to improve the outcome of JMML. In addition, drugs which inhibit the RAS signal transduction have been developed, which are less toxic and will improve outcome in the near future.
Keywords: Juvenile myelomonocytic leukemia (JMML), RAS pathway, 5-Azacitidine, Tipifarnib
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April 2018, 25 (1)
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  • In-sang Jeon