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1378 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1379

did not predict for outcomes in those with cytogenetically normal AML BAALC and miR-3151 in cytogenetically normal AML, (2) distinct
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and with wild-type CEBPα, NPM1, and/or FLT3/ITD. Whether these patterns of dual or multiple gene mutation patterns that have prognostic
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patients would benefit from alternate therapies, such as hypomethylat- impact, and (3) concurrence of somatic mutations and transcriptional
ing agents or HSC transplantation, has not been determined. regulators such as interaction between ERG expression and a heptad of
CEBPα Mutation CEBPα is a leucine zipper transcription factor transcriptional factors that maintains a stem cell-like signature. Fur-
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involved in myeloid differentiation. Mutations have been described in thermore, interactions between genetic and epigenetic changes (DNA
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approximately 10 percent of AML patients. Single or double mutations methylation, histone acetylation, histone methylation, and others) are
can occur, and these rarely are associated with FLT3/ITD or with NPM1 anticipated to have prognostic impact. 174,175
mutations. CEBPα-double, but not CEBPα-single, mutation patients had
a significantly better overall survival at 8 years than wild-type, CEBPα- DEREGULATED SIGNALING PATHWAYS
single, or CEBPα-double and FLT3/ITD-positive patients. A multivar-
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iate analysis found that only double-mutant CEBPα was associated with The mutations in AML result in deregulation of any of several signal
a favorable event-free, relapse-free, and overall survival. Double-mutant transduction pathways, which disrupt pathways that ensure the normal
cases were also associated with a unique gene signature as compared with behavior of (1) differentiation and maturation, (2) proliferation, and
single-mutant cases. 155,156 Some AML patients with CEBPα-double muta- (3) survival signals in hematopoietic cells. The pathways involved are
tions harbor TET2 and GATA2 mutations, which can affect prognostic myriad, but several represent the majority of cases such as the (1) PI3K-
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outlook unfavorably with TET2 or favorably with GATA2 mutations. 157 AKT, (2) RAS-RAF-MEK-ERK, and (3) STAT3 signaling sequences.
IDH1 and IDH2 Mutations The IDHs catalyze oxidative decar- The expectation is that a relative small number of downstream signaling
boxylation of isocitrate into α-hemoglutarate. The nicotinamide adenine pathways mediate the leukemogenic effect of gene mutations, making
dinucleotide phosphate–dependent IDH1 enzyme is encoded by the the potential targets for therapy less diffuse than suggested by the num-
IDH1 gene on chromosome 2q33.3, and the nicotinamide adenine dinu- ber of gene mutations involved in AML.
cleotide phosphate–dependent-dependent IDH2 enzyme is encoded by
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the IDH2 gene on chromosome 15q26.1. Mutations in IDH1 (R132) MODE OF INHERITANCE
or IDH2 (R172) occur in 10 percent of AML patients. 158,159 Both were
found to adversely impact relapse-free survival and overall survival. In most cases, little evidence is seen for a strong influence of inherited
Multivariate analysis showed that IDH mutation conferred an adverse factors. The identical twin of a child with acute leukemia has a height-
impact in those patients with an NPM1 mutation without FLT3-ITD. ened risk of developing the disease. However, the risk appears to be
Favorable genotype cytogenetically normal AML is therefore defined related to intraplacental metastasis and thus falls to the risk of a non-
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as NPM1 or CEBPα mutation with neither a FLT3-ITD nor an IDH1 identical sibling after the first few years of life. The risk of AML
mutation. An IDH1 mutation was also associated with a higher relapse in a nonidentical sibling in the United States is elevated, perhaps two-
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rate and shorter overall survival. Another group found a higher fre- fold to threefold, compared to the risk of AML in unrelated American
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quency of IDH1 and IDH2 mutations in cytogenetically normal AML. children of European descent younger than age 15 years. A regis-
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Both were found to have an unfavorable impact on outcome. IDH1 try study in Sweden showed no significant aggregation in relatives of
was exclusive of other mutations. Serum 2-hydroxyglutarate production patients with AML. An increased risk of AML/MDS was found among
has been found to predict for the presence of IDH1/2 mutations. 162,163 A relatives of patients diagnosed at younger than age 21 years (relative
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level of 700 mg/mL was found to discriminate mutated from nonmu- risk 6.5). Clusters of AML cases in families have been documented,
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tated cases, and those with levels greater than 20 ng/mL at the time of but their frequency is low. Clusters of AML in unrelated persons in
remission had shorter overall survival. Mutant IDH1 has been found a community are uncommon and, when investigated, usually prove
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to accelerate cell-cycle transition and to activate mitogen-activated pro- to be a chance occurrence. Heritable GATA2 mutations may be asso-
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tein kinase signaling. Mutant IDH1 can be inhibited, suggesting this ciated with familial MDS and AML, and loss-of-function germline
may be a therapeutic target. 164 GATA2 mutations (the MonoMAC [monocytopenia and mycobacterial
WT1 Mutations Mutations of the WT1 gene have been reported infections] syndrome) may be associated with primary lymphedema
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in approximately 5 to 10 percent of cytogenetically normal patients with and a predisposition to AML (Emberger syndrome). Mutations of
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AML. Some studies suggest association with a poor prognosis, but CEBPα have been found in familial AML. In one study of 27 families
others have not. WT1 SNP rs 16754 was associated with a favorable with familial MDS/AML, genetic characterization could be shown in
risk, but acquired mutations did not affect the development of com- 10 (four with GATA2 mutations, five with telomerase mutations, and
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plete remission, relapse-free survival, or overall survival. A study of one with mutated RUNX1). Mutations in telomerase RNA (TERC) or
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WT1 mutations in older patients with cytogenetically normal AML also telomerase reverse transcriptase component (TERT) are also associated
185,187
showed poor treatment response across all age-groups and association with familial AML.
with a distinct gene expression signature. 167
EPIDEMIOLOGY
Prognostic Impact of Other Molecular Abnormalities AML is the predominant form of leukemia during the neonatal period
Other methodologies to evaluate genomic aberrations have been but represents a small proportion of cases during childhood and
reported to have prognostic importance beyond the impact of the adolescence. Approximately 20,000 new cases of AML occur annually,
individual mutations described above and in Table 88–2. Abnormal representing approximately 35 percent of the new cases of leukemia in
genome-wide single nucleotide polymorphisms have adverse prognosis the United States each year. Approximately 12,000 patients with AML
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in patients with AML and a normal karyotype. Expression signatures in the United States die each year as a result of the disease. The inci-
of cytokines and chemokines have an independent prognostic impact in dence rate of AML is approximately 1.5 per 100,000 in infants younger
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AML. Profiling transcriptional pathways may have prognostic impor- than 1 year of age, decreases to approximately 0.4 per 100,000 children
tance in AML as well. 170 ages 5 to 9 years, increases gradually to approximately 1.0 persons per
There is also interplay among molecular aberrancies in AML. 100,000 population until age 25 years, and thereafter increases expo-
These include: (1) gene interaction with a microRNA; for example, nentially until the rate reaches approximately 25 per 100,000 persons

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