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1376 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1377

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stratification. Some of these signatures have 24 genes, and some have miscellaneous 3q abnormalities. These generally have an unfavorable
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a seven gene-epigene score. Some have relied on genetic proflilng, prognosis. 118
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some on expression of a subset of molecular mutations, and some Monosomal Karyotype A monosomy has been associated with
have combined epigenetic and genetic markers. Prognostic models of decreased chance of achieving remission or of survival, especially when
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AML based solely on molecular markers have been proposed. In one, combined with TP53 mutations. 119,120
PML-RARa or CEPBA double mutations were very favorable (overall
survival [OS] at 3 years of 83 percent), RUNX1-RUNX1T1, CBF- OTHER ACQUIRED MUTATIONS
B-MYH11, or NPM1 (nucleophosmin-1 mutation) without FLT3-ITD Approximately 45 percent of AML cases have a normal karyotype.
(OS of 62.6 percent), intermediate with no mutation allowing assign- Sequencing has shown that mutations in NPM1, DNMT1, FLT3,
ment to other groups (OS of 44 percent), MLL-PTD or RUNX1, or KIT, CEBPA, TET2, and others may have diagnostic and prognos-
ASXL1 mutation (OS of 22 percent), and very unfavorable, TP53 muta- tic implications. When genomes of APL with a known founder event
tion (OS at 3 years, 0 percent). (PML-RARa) are sequenced and compared with normal karyotype
AML and exomes of HSCs from normal donors, most mutations in
Chromosome Markers AML genomes are random events that occurred in HSC before the
In general, those patients with changes involving CBF, that is, t(8/21), initiating mutation occurred. As the clone expands, one or two addi-
inv(16), t(16;16), or t(15;17), a feature of acute promyelocytic leukemia tional, cooperating mutations may result in development of a leuke-
(APL), are considered predictors of a more favorable outcome. Those mia, and these clones may acquire additional mutations, leading to
with complex karyotype, 11q23, t(6;9), abnormalities of chromosome 5 subclones. DNA sequences of leukemia cell and normal skin cell
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or 7 or inv3 (t3;3) are associated with a poor outcome. The remainder genomes of a patient with AML showed 12 acquired mutations within
of cytogenetic abnormalities and those patients with a normal karyo- coding sequences of genes and 532 somatic point mutations in con-
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type are considered of intermediate risk. These are determined by the served or regulatory portions of the genome. When whole-genome
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behavior of the average of very large groups of patients and confidence or whole-exome sequencing was performed in 200 AML cases, it was
intervals are not calculated. Patients with favorable cytogenetic patterns found that an average of only 13 mutations occurred in the genes. Only
may have poor outcomes and those with less favorable patterns may do a total of 23 genes were mutated. There were nine categories of genes
better than anticipated. thought relevant for pathogenesis: (1) transcription-factor fusions, (2)
Deletions of all or part of a chromosome (e.g., chromosome 5, 7, or nucleophosmin, tumor-suppressor, (3) DNA methylation-related, (4)
9) or additional chromosomes (such as trisomy 4, 8, or 13) are common signaling, chromatin-modifying, (5) transcription-factor, (6) cohe-
cytogenetic abnormalities (Chap. 11), although the specific causative sion-complex, and (7) spliceosome-complex genes. Many of these genes
oncogenes or tumor-suppressor genes in these latter circumstances had patterns of cooperation and mutual exclusivity. Table 88–2 lists
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have not been defined. Deletions in chromosomes 5 and 7 and complex commonly mutated genes in cytogenetically normal AML in order of
cytogenetic abnormalities are associated with a worse prognosis and are decreasing frequency.
increased in frequency in older patients and cases of AML following Nucleophosmin-1 Mutations NPM1 mutations are the most fre-
cytotoxic therapy compared to de novo cases. Because the genes resid- quent genetic alterations in AML, found in approximately half of patients
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ing on the undeleted homologous segment of chromosome 5 are not with a normal karyotype. 124,125 The mutation in exon 12 results in loss of
mutated, an epigenetic lesion, such as hypermethylation of a gene allelic the residue that requires its binding to nucleoli such that the NPM1 pro-
to one on the deleted segment on chromosome 5, may contribute to the tein is abnormally localized to the cytoplasm. Studies show that mutant
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leukemogenic event. NPM1 without FLT3-ITD represents a favorable prognostic marker.
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In APL, PML-RAR-α fusion protein represses retinoic acid-induc- NPM1 mutations also have a favorable prognostic impact in older
ible genes, which prevent appropriate maturation of promyelocytes. The patients. Mutated regions of NPM1 elicit T-cell responses which might
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induced disruption, which involves corepressor–histone deacetylase indicate that immunotherapy could have a role in these mutated cases. 129
complexes, results in the leukemic phenotype (see “Acute Promyelocytic FLT3 Mutations FLT3 encodes a tyrosine kinase receptor in
Leukemia” below). 109,110 normal myeloid and lymphoid progenitors. ITD of FLT3 on chro-
Patients with CBF leukemias are younger on average and in addi- mosome 13 occurs in approximately 25 percent of adult AML cases,
tion to t(8;21) or inv(16)/t(16;16) may have RUNX1/RUNX1T1 and but occurs more frequently in cases of AML with normal cytogenetic
CBFB/MYH11 oncogenes. The cure rate in these so-called good- patterns, monocytic phenotype, and PML-RAR-α or DEK-CAN
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risk patients is only approximately 55 percent, however. Patients with translocations. 124,125,130 The FLT3-ITD mutation confers a poor prognosis
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CBF leukemias expressing KIT have a worse prognosis. In the case of if the ratio of mutant to wild-type expression is high. 130–132 FLT3-ITD
inv(16)/t(16;16), different fusion transcripts can be formed, and these expression is often higher at relapse. FLT3-ITD upregulates MCL-1 to
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may have associated with KIT mutations and other abnormal chromo- promote survival of AML stem cells through signal transducer and acti-
somal associations with differing prognosis, possibly from activation vator of transcription (STAT) 5 activation. FLT3-ITD adversely affects
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of caspase activity. Secondary genetic changes in inv(16) or t(16;16) the outcome of an allogeneic stem cell transplant, but more than half of
cases may have an impact on prognosis. RAS, KIT, FLT3-internal tan- patients harboring this mutation who receive transplants can survive
dem duplication (ITD), and FLT3-TKD each affect prognosis. FLT3- leukemia free for 2 or more years. Point mutations in the tyrosine
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TKD, trisomy 8, age, and therapy-related AML were associated with kinase domain (TKD) of FLT3 (FLT3-TKD) mutations occur in approx-
worse prognosis. In t(8;21) leukemias, epigenetic silencing of microR- imately 6 percent of AML cases and have little impact on outcomes. 136
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NA-193a activates the PTEN/PI3K signaling pathway, and wild-type DNMT3A Mutations The DNMT3A gene encodes a DNA meth-
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RUNX1 can attenuate nuclear factor-kappaB (NF-κB) signaling, events yltransferase isoform. The process of DNA methylation involves the
not present in the t(8;21) translocation leukemias. 116 addition of a methyl group on a cytosine residue at a C-G site. If this
3q Abnormalities EVI1 and MDS1/EVI1 expression in AML methylation happens in the promoter region of a coding gene, the gene
is associated with poor prognosis and is a distinct entity. These chro- will be silenced. The DNMT enzymes contribute to leukemogenesis by
mosome 3 abnormalities are found in only approximately 4 percent of mediating tumor suppressor gene silencing. DNMT3A mutations have
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AML cases. These include inv(3) or t(3;3), t(3q26), t(3q21), and other been found in approximately 20 percent of AML patients with normal

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