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Juvenile myelomonocytic leukemia

Authors
Emi H Caywood, MD
E Anders Kolb, MD
Section Editor
Julie R Park, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative/myelodysplastic disorder of infancy and childhood that is manifest as increased infiltration of the peripheral blood, bone marrow, and viscera by abnormal myelomonocytic cells. The vast majority of patients with JMML have somatic and/or germline mutations of genes within the RAS/MAPK signaling pathway. Allogeneic hematopoietic cell transplantation is the only curative therapy for JMML.

The clinical manifestations, diagnosis, prognosis, and treatment of JMML will be reviewed here. Chronic myelomonocytic leukemia (CMML) and chronic myeloid leukemia (CML) are discussed separately. Overviews of myelodysplastic syndromes and myeloproliferative neoplasms are discussed separately. (See "Chronic myelomonocytic leukemia" and "Clinical manifestations and diagnosis of chronic myeloid leukemia" and "Clinical manifestations and diagnosis of the myelodysplastic syndromes" and "Overview of the myeloproliferative neoplasms".)

PATHOGENESIS

Although much is known about the underlying molecular defects in JMML, the precise mechanisms by which these abnormalities cause this aggressive leukemia remain to be fully elucidated. The vast majority of children with JMML have somatic and/or germline mutations of genes involved in the RAS/MAPK signaling pathway. The resultant pathologic activation of signaling causes hypersensitivity of myeloid progenitor cells to the granulocyte-monocyte colony stimulating factor (GM-CSF) [1-4]. In vitro hypersensitivity of monocyte/macrophage colonies to GM-CSF long represented a diagnostic tool for JMML, and is still used as a minor diagnostic criterion for those patients without an identified underlying molecular defect. (See 'Diagnosis' below.)

Mutations in NF1, PTPN11, KRAS, NRAS, or CBL are found in more than 90 percent of patients with JMML. Alterations of JAK2, TET2, RUNX1, ASXL1, and FLT3, which are commonly associated with myeloproliferative neoplasms (MPNs) of adulthood, are rarely seen in JMML [1,5-9]. In most cases, the mutations associated with JMML are mutually exclusive within a given individual, suggesting that a mutation in any one of these genes is sufficient to activate the signaling pathway and drive the proliferation of JMML cells [2]. Whole exome sequencing has detected secondary mutations of other signaling molecules in a minority of patients, and these secondary mutations may be associated with tumor progression and worse clinical outcomes [10].

DNA hypermethylation at several target genes has been observed in JMML, and this phenomenon may contribute to treatment resistance [11,12]. Although some of the proposed targets of epigenetic silencing are involved with cell proliferation (eg, CDKN2B, RASA4), it is unknown whether these contribute to the pathogenesis of the malignant phenotype or are simply epiphenomena (ie, collateral effects) of a broader hypermethylation phenotype [13].

                                  

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Literature review current through: Apr 2017. | This topic last updated: Apr 27, 2017.
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