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Chapter 58 Pathobiology of Acute Myeloid Leukemia 917

while the C-terminal portion is replaced by a fusion partner. More as complex karyotype, which typically has at least three or more distinct
than 70 unique fusion partners have been identified, including chromosomal abnormalities. Common abnormalities include those
AF4, AF9, AF10, and ENL; these can interact with and recruit involving chromosomes 5 and 7, particularly in AML arising out of
the histone methyltransferase disruption of telomeric silencing 1-like the background of MDS, and each of which are seen in approximately
(DOT1L), which methylates H3K79, and results in the expression of 5% to 10% of patients with AML. Enhancer of zeste 2 polycomb
HOXA genes implicated in leukemic transformation. Expression of repressive complex 2 subunit (EZH2) is a histone methyltransferase
the MLL-AF9 fusion in mice generates AML with high penetrance that may play a role in leukemogenesis via haploinsufficiency in the
and short latency. Another mechanism by which MLL plays a role setting of loss of material from the long arm of chromosome 7. Inter-
in leukemia is through an in-frame partial tandem duplication of stitial deletions on the long arm of chromosome 5 at 5q33.1 are associ-
exons 5–12 (MLL-PTD). Mouse knock-in models with MLL-PTD ated with the 5q minus syndrome, which has a low risk of progression
develop acute leukemias characterized by overexpression of Hox to sAML. RPS14 and miR145/146a have been implicated in the
genes and an increase in H3/H4 acetylation with associated H4K4 pathogenesis of this syndrome. In contrast, deletions involving a more
methylation. proximal region at 5q31.2 are associated with higher risk of sAML
transformation. Most chromosome 5 deletions in high-risk MDS and
AML are large, including most of the long arm or the entire chromo-
Rare Translocations some. Many genes have been implicated in diseases associated with
these larger deletions, including APC, CTNNA1, HSPA9, EGR1, and
Less common cytogenetic abnormalities implicated in the pathogen- NPM1.
esis of AML include the t(6;9), which fuses the DEK oncogene, which Loss of chromosome 17p, including the TP53 locus at 17p13, is
encodes a DNA binding protein involved in transcription regulation associated with complex cytogenetics as well as abnormalities in
and introduction of supercoils, with Nucleoporin 214 (NUP214 or chromosome 5 and 7. Indeed, there appears to be cooperativity
CAN), which encodes a nuclear envelope pore protein that regulates between 17p alterations and deletions at chromosome 5q13 at the
nuclear/cytoplasmic transport. This rearrangement is found in site of SSBP4, another tumor suppressor gene, which may influence
approximately 1% of patients with AML and is associated with a poor the progression to leukemia. Alterations in 17p are enriched in
prognosis. It typically occurs as a sole chromosomal rearrangement; patients with alkylator-associated tAML and sAML rising from an
however, there is a high frequency of concurrent mutations in FLT3- underlying MPN or MDS. In contrast to AML with balanced
ITD. The fusion retains most of the open reading frame from both translocations, leukemias that develop in the context of 17p altera-
proteins, but the molecular consequences of the fusion protein are tions are characterized by greater genomic instability.
not well understood. Retroviral transduction of long-term HSCs Common trisomies in AML include somatic acquisition of
generates leukemias after transplantation into mice. trisomy 8 and trisomy 21, seen in approximately 10% and 3% of
t(3;3)(9q21;q26.2) and inv(3)(q21q26.2) are included in the “acute patients, respectively. Trisomy 8, the most common chromosomal
myeloid leukemia with recurrent cytogenetic abnormalities” category gain seen in AML, may contribute to leukemogenesis via amplifica-
in the WHO classification. Collectively, the inv(3)/t(3;3) rearrange- tion of MYC, which is located at chromosome 8p24 and is implicated
ments are present in less than 5% of AML cases and are associated with in a number of malignancies including AML. Acquired trisomy 21,
poor survival. These rearrangements juxtapose EVI1 (MECOM) with similar to AML in Down syndrome, appears to progress to AML via
regulatory elements of the RPN1 locus. EVI1 interacts directly with the subsequent acquisition of mutations in RUNX1 or GATA1.
DNA methyltransferase 3A (DNMT3A) and DNMT3B, which may Unlike Down syndrome, acquired trisomy 21 often occurs in con-
account for the distinct DNA hypermethylation signature associated junction with other cytogenetic aberrations, in particular with
with dysregulated EVI1 expression. Patients with this translocation complex cytogenetic rearrangements.
may have preceding MDS, and often the bone marrow morphology
shows multilineage dysplasia with atypical megakaryocytes.
t(8;16)(p11;p13) is a rare translocation that occurs in de novo AML Recurrently Mutated Genes
and topoisomerase II-associated tAML. The disease typically has a FAB
M4 or M5 phenotype, and patients often present with extramedullary For many patients, a recurrent chromosomal abnormality cannot be
disease, coagulopathy, and hemophagocytosis. This translocation fuses detected by either cytogenetic analysis or fluorescence in situ hybrid-
two histone acetyltransferases: KAT6A (also known as MOZ or ization, using probes for common rearrangements and copy number
MYST3) and CREB binding protein. The fusion protein binds to alterations. This group of patients with normal cytogenetics accounts
DNA and the colocalized proteins result in upregulation of the HOX for approximately 45% of AML cases and has historically been catego-
genes HOXA9 and HOXA10, as well as their cofactor, MEIS1. rized as having intermediate prognosis with standard treatment.
The t(1;22) involving one twenty two (OTT; or RNA-binding Molecular testing of this group, as well as patients in other cytogenetic
motif protein 15 [RBM15]) and megakaryocytic acute leukemia risk groups, has identified a number of recurrent genetic alterations
(MAL or MKL1) is a rare translocation found in infant acute mega- that play critical roles in AML pathogenesis, prognosis, and response
karyocytic leukemia. MAL functions as a transcriptional coactivator to therapy. On average, AML genomes contain fewer somatic muta-
of DNA-bound serum responsive factors (SRFs) and triggers histone tions compared with other adult cancers (fewer than 20 mutations
modifications, including acetylation of H3K9. The translocation in protein-coding genes per case). Genes that are mutated across
generates the OTT-MAL fusion protein, which alters MAL function, multiple AML cases at a frequency higher than expected by chance
resulting in SRF-directed expression of MYL9 and MMP-9, which are more likely to be biologically relevant. AML mutations can be
play a role in megakaryocyte development and migration, and may categorized according to the type of gene that is affected and the
contribute to the phenotype of t(1;22) megakaryocytic leukemia. functional impact of the mutation. Many gene mutations cooperate
Mice engineered to express OTT-MAL have altered megakaryocyte with other alterations, including the large-scale copy number changes
development and dysregulated NOTCH signaling. With concurrent and rearrangements described earlier (Fig. 58.2).
activating mutations in MPL, these mice develop acute megakaryocytic
leukemia.
Cytokine Signaling
Amplifications and Deletions A number of mutations have been identified that result in altered signal
transduction, enhancing leukemic cell proliferation and survival.
Recurrent cytogenetic abnormalities in AML also include somatically These include mutations in the fms-related tyrosine kinase 3 (FLT3)
acquired chromosome copy or segment gains, chromosomal monoso- gene, RAS genes, and KIT. Mutations in FLT3 can occur either as
mies, as well as the accumulation of karyotypic abnormalities, classified an in-frame internal tandem duplication within the juxtamembrane