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Chapter 62 Acute Myeloid Leukemia in Children 987

gain of function to catalyze the NADPH-dependent reduction of an inactive GDP-bound state and an active GTP-bound state.
α-KG to 2-hydroxyglutarate (2-HG). The altered activity of the Somatic mutations occur at amino acid residues, which impair their
enzyme leads to an increase in the level of 2-HG, which has pleotropic intrinsic GTPase activity and also confer resistance to GTPase-
effects including the inhibition of the enzymatic activity of the activating proteins leading to persistence of a GTP-bound (and
α-KG-dependent enzyme TET oncogene family member 2 (TET2), therefore active) state. Active RAS mediates effects through a multi-
responsible for catalyzing the conversion of 5-methylcytosine to tude of downstream effector pathways including RAC, PI3K, RAF,
5-hydrozymethylcytosine. Loss-of-function mutations of TET2 have RAL, and PKC, all of which confer abnormal functional properties
also been identified in a variety of hematopoietic malignancies includ- in cancer cells. These pathways affect cell cycle progression, promote
ing MDS, myeloproliferative neoplasms and AML. Interestingly, survival, and stimulate actin reorganization and vesicle trafficking, all
mutations in IDH1/2 and TET2 appear to be mutually exclusive, of which have been shown in various model systems to contribute to
confirming a common downstream effect of these lesions. Alterations RAS-induced tumorigenesis. In AML, cooperating lesions found in
of the enzymatic activity of TET2, either through direct mutations NRAS mutant cases include NPM1, C/EBPA, PML-RARA, MLL
or mutation of IDH1/2, lead to enhanced self-renewal of hematopoi- rearrangements, RUNX1-ETO, and CBFB-MYH11. In a pediatric
etic progenitors and an expansion of the stem cell and progenitor cell cohort of 111 AML cases, activating mutations in NRAS were found
compartment, and thereby directly contribute to leukemogenesis. in 45%, 44%, and 24% of RUNX1-ETO, CBFB-MYH11, and MLL
rearranged cases, respectively.
FMS-like Tyrosine Kinase 3
FMS-like tyrosine kinase 3 (FLT3, FLK2) is a class III receptor CCAAT Enhancer-Binding Protein Alpha
tyrosine kinase that is normally expressed in early hematopoietic CCAAT enhancer-binding protein alpha (C/EBPα) is a transcrip-
+
+
progenitors that are CD34 /c-Kit . When bound by its ligand (FLT3 tion factor that contains two N-terminal transcriptional activation
ligand or FL) the receptor dimerizes, leading to activation of the domains (TAD1 and TAD2) and a C-terminal DNA-binding basic
receptor’s intrinsic tyrosine kinase activity. The activated kinase region followed by a leucine zipper domain that mediates homo-
signals through a variety of pathways including the phosphatidylino- and hetero-dimerization with other CEBP family members. DNA
sitol 3-kinase (PI3K) and RAS signal-transduction cascades through binding requires dimerization and is critically dependent on the
phosphorylation of cytoplasmic substrates. Two major classes of distance between the leucine zipper domain and the DNA-binding
FLT3-activating mutations have been identified in AML, internal basic region. CEBPA encodes an mRNA that contains alternative
tandem duplication (ITD) in the juxtamembrane domain and point translation initiation sites resulting in two major protein isoforms:
mutations in the tyrosine kinase domain (TKD). Both classes of the fully translated C/EBPα (p42), and an N-terminally truncated
mutations result in ligand-independent constitutive activation of the protein (p30) lacking the N-terminal transactivation domain TAD1.
receptor’s kinase activity and induce factor-independent growth of In the hematopoietic system, CEBPA is expressed in myeloid
the murine pro-B–cell line Ba/F3. FLT3 mutations are frequent progenitors and granulocytes but not macrophages, and has been
cooperating lesions, being found not only in cytogenetically normal shown to regulate the expression of many myeloid genes. Condi-
AML, but in APL, CBF AML, and MLL-rearranged leukemia as well. tional knockout of Cebpa in adult mice blocks the transition from
The FLT3-ITD mutation results from a fragment of the common myeloid progenitors to the more differentiated granulo-
juxtamembrane-domain coding sequence that is duplicated and cyte monocyte progenitor, leading to an accumulation of myeloid
inserted, the length of which varies from 3 to 400 bp. The juxtamem- blasts.
brane domain is a negative regulator of the kinase activity and the Mutations that reduce the transcriptional activity of C/EBPα
ITD leads to a disruption of this autoinhibitory activity. As a result occur in between 5% and 14% of AML patients, and are primarily
of the disruption of this domain, the mutant FLT3-ITD undergoes seen in FAB-M1/2 AMLs with a normal karyotype. Two classes
ligand-independent dimerization and tyrosine autophosphorylation, of CEBPA mutations have been defined: mutations that occur
and this constitutively active tyrosine kinase activates the downstream within the first 300 bp of the CEBPA gene and result in frame-
targets that are normally regulated by the native receptor. Transplan- shifts or stop codons that eliminate expression of the p42 isoform
tation of bone marrow cells transduced with FLT3-ITD into mice but have no effect on the translation of p30; and mutations in
leads to a myeloproliferative disorder but not leukemia, underscoring the 3′ end of the gene that result in in-frame insertions or dele-
the importance of cooperative mutations in FLT3-ITD–positive tions that disrupt the relationship of the basic and leucine zipper
malignancy. In a study of 144 cases of newly diagnosed adult AML, domains and alter DNA-binding activity. The most frequent pattern
24 out of 28 FLT3-ITD–positive cases had second mutations/ seen in patients is a combination of the two types of mutations,
alterations, the most frequent of which were mutations of NPM1, one on each allele. Knock-in mice that eliminate p42 transla-
MLL-PTD, CEBPA, and PML-RARA. tion while allowing expression of p30 have been generated, and
FLT3-TKD mutations occur in the activation loop of the kinase these mice uniformly die of AML by 60 weeks of age, providing
domain, leading to constitutive activation. In a wild-type setting, direct evidence that Cebpa mutations contribute to the process of
ligand-induced activation of FLT3 causes an active configuration to leukemogenesis.
form, allowing kinase activity. The TKD mutations interfere with the
inhibitory loop and thus are similar to ITD in disrupting the regula-
tion of signaling, but differ in that they do not require dimerization CLINICAL AND LABORATORY MANIFESTATIONS
for constitutive activation. While both mutations lead to constitutive AND DIAGNOSIS
activation of AKT and extracellular signal-related kinase (ERK)1/2
from the PI3K and RAS signaling cascades, respectively, data suggest Most children with AML have signs and symptoms of bone marrow
that strong signal transducer and activator of transcription (STAT5) failure, including pallor, fatigue, bleeding, bruising, and infection.
activation is only observed in FLT3-ITD cells. Hepatosplenomegaly, lymphadenopathy, and bone pain are common,
but usually less prominent than in children with ALL. Because of the
RAS acute nature of the process, weight loss and other signs of chronic
RAS proteins couple receptor activation with downstream effector disease are rare. In some cases, the predominant clinical signs result
pathways, altering proliferation, differentiation, and apoptosis. not from bone marrow disease, but from extramedullary myeloid
Overall, approximately 30% of cancers express a mutant or so-called tumors, referred to as chloromas or granulocytic sarcomas, which most
oncogenic RAS. Three RAS genes are encoded in the human genome: often arise in the orbital or spinal regions. Other clinical manifesta-
HRAS, KRAS, and NRAS, and the frequency of mutations for these tions include gingival hypertrophy, commonly seen in AML cases
genes vary significantly between cancer types. In myeloid leukemia, with a monocytic component, and skin or subcutaneous nodules.
NRAS mutations predominate, followed in frequency by KRAS, while Cutaneous lesions may be single or multiple violaceous papules or
HRAS mutations have not been reported. RAS proteins cycle between nodules, are most common in infants, and may be mistaken for the