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Chapter 63 Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children 995

Mutant receptor tyrosine kinases:
TEL-PDGFRβ (CMML), CKIT and FLT3 (AML)

RAS-GDP
Grb2 SOS
Shc
JAK Gab2 Neurofibromin
SHP-2 Ras-GTP* (JMML)
STAT
(JMML)
(AML, JMML, CMML, MDS)

BCR-ABL
“Ras pathway” lesions:
JAK2 mutations: (CML) Effector pathways AML 60%
PV >90% MPD
ET 50% JMML 75%
CIMF 50% CMML 40%
CMML 10% CML >95%

Fig. 63.1 OVERVIEW OF RAS SIGNALING WITH MOLECULES HARBORING MUTATIONS IN
PATIENTS WITH MYELOID MALIGNANCIES. AML, Acute myeloid leukemia; CML, chronic myeloid
leukemia; CMML, chronic myelomonocytic leukemia; ET, essential thrombocythema; GDP, guanosine
diphosphate; GTP, guanosine triphosphate; JAK, Janus-activated kinase; JMML, juvenile myelomonocytic
leukemia; MDS, myelodysplastic syndromes; MPD, myeloproliferative disorder; PV, polycythemia vera.

Class I mutations Class II mutations in mRNA spicing genes or DNA methylation genes) including
transcription factors (RUNX1, ETV6, PHF6, GATA2), kinase signaling
Confer proliferative and/or Impaired differentiation genes (NRAS, KRAS, JAK2, CBL), and cohesion genes (STAG2, SMC3,
survival advantage, but and apoptosis RAD21). Finally, approximately 10% of adult patients have no muta-
do not affect differentiation tions detectable. This remarkable improvement in the understand-
32
ing of the genetic events underlying adult MDS is leading to improved
Examples: Examples: methods of risk-group stratification and prognosis (e.g., TP53 muta-
tions are associated with adverse disease features and outcomes). 33–35
FLT3, ALM, c-kit, oncogenic AML/ETO,PML/RARα, The patterns of genetic and karyotypic abnormalities in children
Ras, BCR/ABL, CEBPα, CBF, HOX family with MDS are increasingly distinctive from that of adults. Although
TEL/PDGFBR, PTPN11 members, MLL rearrangements, a few karyotypic abnormalities are shared (e.g., 7/7q−), many that
CBP/P300, co-activators TIF1 are common in adults are only rarely found in children (e.g., 5q−).
Importantly, mutations in mRNA spicing genes and other genes are
only rarely found in children with de novo and secondary MDS. 36–39
AML
Mutations in epigenetic genes that control DNA methylation and
histone function are also only rarely identified in children, making
Proliferation and
survival advantage their role in MDS uncertain. For example, although mutations in
TET2 are identified in 20%–25% of adults with MDS, only one out
Impaired differentiation of 19 children with refractory cytopenia of childhood (RCC) had a
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mutation in TET2. Instead, the genetic abnormalities in children
with MDS are most often those associated with inherited BM failure
syndromes and other genetic disorders (FANC member genes, DKC,
MPS MDS TERT, TREC, WAS, GATA-2, SBDS, etc.).
Finally, three exceedingly rare familial forms of MDS/AML are
Proliferation and survival Impaired differentiation
advantage BM failure associated with mutations in RUNX1/AML1 (familial platelet disor-
der with a predisposition to AML), CEBPα (familial AML), and
GATA-2. 39,41–43
Fig. 63.2 COOPERATING MUTATIONS IN ACUTE MYELOID
LEUKEMIA, MYELOPROLIFERATIVE SYNDROMES, AND MYELO-
DYSPLASTIC SYNDROMES. AML, acute myeloid leukemia; BM, Bone Classification
marrow; MDS, myelodysplastic syndromes; MPS, myeloproliferative
syndromes.
Until recently, MDS in children was poorly defined, characterized,
classified, and reported. In fact, MDS was not included in the
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International Classification of Childhood Cancer until 2005. Also
contributing to this lack of information was the use of classification
and prognostic systems designed for adults that have had limited