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Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations

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Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myelodysplastic/myeloproliferative disorder that affects young children. It is characterized by hypersensitivity of JMML cells to granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. The pathogenesis of JMML seems to arise from constitutional activation of the GM-CSF/RAS (a GTPase) signaling pathway, a result of mutations in RAS, NF1, PTPN11, and CBL that interfere with downstream components of the pathway. Most patients with JMML usually experience an aggressive clinical course, and hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment, although the high rates of relapses and graft failures are of great concern. In contrast, a certain proportion of patients experience a stable clinical course for a considerable period of time, and sometimes the disease even spontaneously resolves without any treatment.

Recent studies have provided us with increased knowledge of genotype-phenotype correlations in JMML, and suggested that differences in clinical courses may reflect genetic status. Thus, genotype-based management is of current international interest, especially for JMML with RAS mutations. Cumulative evidence suggests that RAS mutations can be related to favorable clinical outcomes, and HSCT may not have to be a mandatory therapeutic option for a portion of patients with this mutation, although a consensus regarding genotype-based management has not yet been achieved. Further efforts toward identifying which patients who will do well without HSCT are required.

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Acknowledgments

No sources of funding were used to assist in the preparation of this article. The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Children’s Medical Center, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Nao Yoshida

  2. Department of Pediatrics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Sayoko Doisaki &  Seiji Kojima

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  1. Nao Yoshida
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  2. Sayoko Doisaki
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Correspondence to Seiji Kojima.

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Yoshida, N., Doisaki, S. & Kojima, S. Current Management of Juvenile Myelomonocytic Leukemia and the Impact of RAS Mutations. Pediatr Drugs 14, 157–163 (2012). https://doi.org/10.2165/11631360-000000000-00000

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