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998 Part VII Hematologic Malignancies

TABLE Diagnostic Criteria for Juvenile Myelomonocytic in NRAS or KRAS (25%), 125–127 mutations in the PTPN11 gene (see
128–131
63.1 Leukemia Fig. 63.1) (35%), and mutations in CBL (10%–15%). This
synopsis reflects decades of research, beginning with the seminal
Category 1 Category 2 Category 3 observation that JMML is associated with neurofibromitosis type 1
All of the Following: At Least 1 of the At Least 2 of the (NF1). A rough comparison of incidence rates suggests that NF1
Following: Following: carries a 500-fold increased risk of acquiring JMML. At a molecular
• Splenomegaly a • Somatic mutation • Circulating myeloid level, these children inherit a defective allele of the NF1 gene, which
• AMC >1000/µL in RAS or PTPN11 precursors encodes a negative regulator of Ras named neurofibromin. In
• Blasts in PB/BM • Clinical diagnosis • WBC >10,000/µL JMML, the normal allele is lost as a somatic event in the initiating
<20% of NF1 or NF1 • Increased Hgb F cell, most often by loss of heterozygosity in which the overall copy
• Absence of the gene mutation for age number remains unchanged (uniparental isodisomy). This completely
t(9;22) BCR/ • Homozygous • Clonal cytogenetic ablates neurofibromin and thereby increases Ras activity.
ABL fusion gene mutation in CBL abnormality Such interplay of inherited and somatic mutations is also relevant
• Monosomy 7 excluding to the other JMML genes. Germline mutations in PTPN11 cause
monosomy 7 Noonan syndrome (NS), a common genetic condition that overlaps
• GM-CSF phenotypically with NF1 and sometimes includes a mild JMML-like
hypersensitivity myeloproliferative syndrome. This finding led directly to the discov-
ery of somatic PTPN11 mutations in sporadic JMML, a lesion now
The diagnosis of juvenile myelomonocytic leukemia is made if a patient meets
all of the Category 1 criteria and one of the Category 2 criteria without needing recognized as the most common pathogenic mutation in this disease.
to meet the Category 3 criteria. If there are no Category 2 criteria met, then the Furthermore, rare germline mutations in KRAS have also been associ-
Category 3 criteria must be met. ated with related genetic syndromes including NS and cardiofacio-
a For the 7%–10% of patients without splenomegaly, the diagnostic criteria must 132–137
include all other features in Category 1 AND one of the parameters in Category cutaneous syndrome. The PTPN11 and KRAS mutations
2 OR no features in Category 2 but two features in Category 3. present in the germline generally have less severe biochemical conse-
AMC, Absolute monocyte count; BM, bone marrow; GM-CSF, granulocyte- quences than those in sporadic cases. This suggests that strong signal
macrophage colony-stimulating factor; Hgb F, fetal hemoglobin; NF1, activation is not tolerated during development. Accordingly, the most
neurofibromitosis type 1; PB, peripheral blood; PTPN11,; WBC, white blood common NS-associated PTPN11 alleles have relatively weak effects
cell.
From Chan RJ, Cooper T, Kratz CP, et al: Juvenile myelomonocytic leukemia: A on signal transduction, and the myeloproliferative syndrome in these
report from the 2nd International JMML Symposium. Leuk Res 33:355, 2009. patients is usually transient. 138–140 However, a more recent and com-
prehensive analysis has suggested that a cohort of NS patients may
inherit more deleterious mutations and develop fatal neonatal
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JMML. Thus cytoreductive therapy or HCT may be considered
MYELOPROLIFERATIVE NEOPLASMS for select NS patients with severe disease.
Similar to NF1, mutations in CBL are heterozygous in the germ-
Juvenile Myelomonocytic Leukemia line, with subsequent reduction to homozygosity in hematopoietic
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cells. This contrasts with the lesions described in adults. The het-
erozygous germline mutations appear to cause a genetic syndrome
JMML is classified by the WHO as an overlap of MDS and MPN. It with features that can overlap with NS, termed CBL syndrome or
is an aggressive myeloid malignancy of young children with poor Noonan syndrome-like disorder with or without juvenile myelomonocytic
outcomes to conventional therapies. The diagnostic criteria are leukemia. The phenotypic manifestations of NSLL are variable and
complex (Table 63.1), but recent advances in elucidating the molecu- incompletely penetrant, and they include cryptorchidism, hearing
lar genetics of the disorder demonstrate that approximately 85% of loss, and skeletal abnormalities. Importantly, major vascular abnor-
children will harbor an alteration in one of five genes. Thus there is malities have been described in patients with CBL-mutant JMML,
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now international agreement on the diagnostic criteria (see Table and this could also reflect an NSLL phenotype. As expected for a
63.1), with an emphasis on incorporating these molecular genetic heterozygous mutation, transmission is autosomal dominant,
criteria, as well as a recent definition of common response criteria. 112 although 50% of cases arise spontaneously. 129,131,142–145 In contrast to
the loss of function mutations in NF1, the mutations in CBL selec-
tively inactivate the ubiquitin ligase activity of the Cbl protein while
Epidemiology leaving the molecule otherwise intact. When homozygous, this altera-
tion eliminates the negative regulatory activity of Cbl while sparing
The incidence of JMML in the United States has been estimated as positive signaling functions. 130
0.69–1.2 per million. 4,113 There is a male predominance with a It has been speculated that the 15% of patients without mutations
median age of diagnosis of 1.8 years. The apparent incidence and in the five major JMML genes have heretofore undetected mutations
demographic distribution may change in coming years because of that also activate Ras signaling. In recent genomic studies, rare muta-
refinement of diagnostic techniques such as molecular testing. In tions in SH2B3, RRAS, RRAS2, RAC2, or JAK3 seem to be consistent
particular, mutation analysis may identify patients with less aggressive with this idea. 146–148 Collectively, these data support the idea that
disease or at a younger age. hyperactive Ras is essential for initiation of JMML, but suggest that
initiating mutations beyond the five major genes will be diverse and
infrequent.
Pathogenesis These so-called Ras pathway or driver mutations are largely mutu-
ally exclusive, supporting the idea that each provides a similar func-
Early clonality studies suggested that JMML arose at the level of at tion in JMML. However, patients with two such lesions or duplication
least an immature myeloid precursor cell. 111,114–118 More recent data of the mutant allele have been reported, typically co-occurring in the
suggest that JMML may arise in a pluripotent stem cell with involve- same cells. 146,147 This likely reflects clonal evolution and positive
ment of the myeloid, erythroid, and megakaryocyte lineages, as well selection for increased Ras signaling even beyond that provided by
as B lymphocytes and T lymphocytes. 111,119–122 This is supported by the initiating mutation. Growing evidence demonstrates that negative
finding pathogenic mutations in immature hematopoietic cells feedback prevents the Ras pathway from being fully activated by a
identified by flow cytometry. 123 single lesion, leading to a dosage effect of mutant alleles on signaling
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Somatic mutations that augment signaling through the Ras outputs. Consistent with predictions from model systems, cases
pathway occur in approximately 85% of JMML patients. These with multiple Ras pathway mutations have a more aggressive clinical
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include biallelic inactivation of NF1 (15%), activating mutations course. 147