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Chapter 63 Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children 999

Genomic studies have also begun to address the question of More overt effects are seen in myeloid and erythroid progenitor
whether mutations outside the Ras pathway contribute to the patho- cells, as manifested clinically by the circulation of immature erythroid
genesis of JMML. 123,146–148 A wide variety of so-called secondary and myeloid forms in the peripheral blood. In normal hematopoiesis,
mutations have now been recognized. They are primarily associated proliferative myeloid precursors are only present in the bone marrow
with relapse of JMML after HCT, or with transformation to AML. and are strictly dependent on exogenous cytokines. By contrast,
However, they often can be detected at a low level in the blood or myeloid colonies arise from cultures of either blood or bone marrow
bone marrow when JMML is first diagnosed. This suggests that clonal from JMML patients, and they often do not require additional
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evolution selects for chemotherapy resistance and eventually leukemic cytokines. Importantly, they uniformly demonstrate a hypersensi-
transformation. This is supported by the striking observation that tive dose-response curve to the cytokine granulocyte-macrophage
secondary mutations of any kind have a major prognostic impact, colony-forming factor (GM-CSF). Finally, aberrant differentiation
even when they are present in a very small proportion of hematopoi- generates excessive monocytes and insufficient mature erythrocytes.
etic cells at diagnosis. Although the mechanisms underlying abnormal hematopoiesis in
In the few JMML cases in which clonal history has be inferred, JMML remain under investigation, both cell-intrinsic and cell-
mutations appear to be acquired sequentially, beginning with a Ras extrinsic mechanisms are likely to contribute.
pathway lesion. This linear evolutionary path contrasts with the Similarly, the precise biochemical signaling events responsible for
highly branched patterns typical of high-grade neoplasms. Thus the MDS/MPN phenotype are poorly understood. Ras proteins
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despite the discovery of a variety of secondary mutations in JMML, potentially signal through a wide variety of effector proteins, but
it remains a disease with much less genetic complexity than most cancer is most closely linked to the Raf/MEK/ERK and PI3K/Akt
cancers. This may have important implications for therapy, as any pathways. Evidence from model systems suggests that each of these
individual patient is likely to harbor a relatively small number of plays an important role in directing the abnormal growth and dif-
distinct subclones that need to be eradicated to achieve cure. ferentiation that defines JMML. Inhibitors of MEK cause substantial
The cellular function of cooperating mutations in JMML is under improvements in MDS/MPN in Kras or Nf1 mutant mice. 165,166
active investigation. Most can be categorized into three groups. Some Similarly, attenuation of PI3K signaling counteracts the effects of
amplify signaling beyond the level provided by the initial Ras pathway mutant Ptpn11 and Kras alleles in mice. 167–169 The relevant down-
mutation. As described earlier, some second mutations directly alter stream targets of these signaling networks in JMML are poorly
core Ras pathway genes. Janus-activated kinase (JAK)/signal trans- characterized, but several studies have implicated specific hematopoi-
ducer and activator of transcription (STAT) signaling is enhanced by etic transcription factors that integrate aberrant upstream signals to
activating mutations in JAK3 or loss-of-function mutations in alter hematopoietic cell fate decisions. 170,171
SH2B3, which encodes the negative regulatory adaptor protein LNK. JAK/STAT signaling is also implicated in JMML. The GM-CSF
Mutations in RRAS, RRAS2, and RAC2 represent a novel signaling receptor requires the nonreceptor tyrosine kinase Jak2 to initiate
complex in JMML that is implicated in regulating the PI3K/Akt signaling. Therefore JAK2 is upstream of Ras as well as STAT5 in
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pathway. Dominant point mutations in SETBP1 remain somewhat this context. STAT5 phosphorylation in myeloid progenitors from
unexplored, but may augment signal transduction by inhibiting the JMML patients is hypersensitive to GM-CSF, mirroring the abnormal
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phosphatase PP2A or regulate gene transcription and strengthen colony forming activity of these cells. The acquisition of JAK3 or
self-renewal programs. Other secondary lesions have broad effects on SH2B3 mutations in advanced JMML also implies involvement of
gene expression, through inactivation of the PRC2 polycomb repres- this pathway in JMML pathogenesis.
sor complex or alteration of spliceosome components. Many of these
genes and cellular functions are also implicated in the pathogenesis
of other myeloid neoplasms such as CMML or AML. Clinical Manifestations

Children with JMML typically present with signs and symptoms
Model Systems attributable to a heavy burden of organ-infiltrating cells that results
in hepatosplenomegaly, lymphadenopathy, and skin rash. As a result
Genetically engineered mouse models of JMML have been based on of the association with neurofibromatosis, patients may also have
directed mutation of Nf1, Kras, Nras, Ptptn11, and c-Cbl. These are café-au-lait spots or juvenile xanthogranulomas. Death is usually the
reviewed in detail elsewhere. 150,151 In general terms, these mice result of organ dysfunction caused by infiltrating cells, infection, or
reproduce many key features of JMML, but penetrance and severity bleeding. Approximately 10%–20% of children progress to a blast-
of disease vary across these models. In an alternative approach, like phase consistent with AML.
induced pluripotent stem cells have recently been generated from
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germline and neoplastic cells from JMML patients. These can be
differentiated into myeloid progenitors that also recapitulate signal Laboratory Manifestations
transduction and cell biology phenotypes characteristic of JMML.
Together, these systems provide a robust set of tools for investigating Laboratory abnormalities may include an elevated white blood cell
the biology of JMML and also enable preclinical testing of novel count with absolute monocytosis, anemia, and thrombocytopenia
therapeutic strategies. (Figs. 63.4 and 63.5). Monocytes, either circulating in the peripheral
blood or in the BM, frequently appear dysplastic. The peripheral
smear shows leukoerythroblastic changes, and there are often circulat-
Cell Biology of JMML ing nucleated red blood cells. Fifty percent of patients may also
present with elevated fetal hemoglobin levels and hypergammaglobu-
Hematopoiesis in JMML is altered in a distinctive way that is much linemia, which is of interest given that there are patients recently
more subtle than in acute leukemias, although nonetheless usually described with autoimmune lymphoproliferative syndromes who also
fatal if not corrected. A consensus has emerged that the disease initi- harbor RAS mutations (see later). International criteria mandate that
ates with a somatic Ras pathway mutation, presumably in a single the BM have fewer than 20% blast cells at diagnosis. Other findings
HSC. This implies that the mutation imparts a competitive advantage typical in the BM may include micromegakaryocytes.
over normal stem cells. This is supported by evidence from multiple
−/−
mouse models. 153–156 Interestingly, however, Nf1 HSCs fail to cause
an overt disease when mixed with wild-type cells, suggesting a limit Differential Diagnosis
to the advantage imparted by Nf1 loss. Furthermore, there is also
evidence that excessive signaling in Ras or phosphatidylinositol Traditionally, establishing a diagnosis of JMML was not easy because
3-kinase (PI3K) induces substantial stress in HSCs. 153,157–162 its clinical and laboratory presenting features can also be associated