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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias.[1] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia. The diagnostic criteria that need to be met for JMML are included in Table 5.[2,3]

Table 5. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML)

Category 1 (all of the following)aCategory 2 (at least one of the following)b,cCategory 3 (two of the following if no category 2 criteria are met)a,d
GM-CSF = granulocyte-macrophage colony-stimulating factor.
a Current World Health Organization (WHO) criteria.
b Proposed additions to the WHO criteria that were discussed by participants attending the JMML Symposium in Atlanta, Georgia in 2008.[2]CBLmutations were discovered subsequent to the symposium and should be screened for in the workup of a patient with suspected JMML.[3]
c Patients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria.
d Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
e Note that only 7% of patients with JMML will NOT present with splenomegaly but virtually all patients develop splenomegaly within several weeks to months of initial presentation.
Absence of theBCR/ABL1fusion geneSomatic mutation inRASorPTPN11White blood cell count >10 × 109 /L
>1 × 109 /L circulating monocytesClinical diagnosis of NF1 orNF1gene mutationCirculating myeloid precursors
<20% blasts in the bone marrowMonosomy 7Increased hemoglobin F for age
Splenomegalyb,e Clonal cytogenetic abnormality excluding monosomy 7b
  GM-CSF hypersensitivity

The pathogenesis of JMML has been closely linked to activation of the RAS oncogene pathway, along with related syndromes (see Figure 1).[2,3] In addition, distinctive RNA expression and DNA methylation patterns have been reported; they are correlated with clinical factors such as age and appear to be associated with prognosis.[4,5]

Figure 1. Schematic diagram showing ligand-stimulated Ras activation, the Ras-Erk pathway, and the gene mutations found to date contributing to the neuro-cardio-facio-cutaneous congenital disorders and JMML. NL/MGCL: Noonan-like/multiple giant cell lesion; CFC: cardia-facio-cutaneous; JMML: juvenile myelomonocytic leukemia. Reprinted from Leukemia Research, 33 (3), Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh, Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium, Pages 355-62, Copyright 2009, with permission from Elsevier.

Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML,[6,7] and up to 14% of cases of JMML occur in children with NF1.[8] Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%),[9,10] NF1 inactivating mutations (approximately 15%–25%),[11] or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[12,13] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[14,15] with many of these cases occurring in children with germline CBL mutations.[16,17]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[16] Some individuals with CBL germline mutations experience spontaneous regression of their JMML, but develop vasculitis later in life.[16]CBL mutations are mutually exclusive with RAS/PTPN11 mutations.[14] Noonan syndrome, which is usually inherited as an autosomal dominant condition, but can also arise spontaneously, is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[3]


WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
This information is not intended to replace the advice of a doctor. Healthwise disclaims any liability for the decisions you make based on this information.
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