Page 1036 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 58 Pathobiology of Acute Myeloid Leukemia 919

murine models, expression of mutant NRAS or KRAS results in a in approximately 20% of patients with de novo AML, but nearly
spectrum of myeloid disease, with variable features of acute leukemia, 30% of patients with a normal karyotype. Nearly 50% of the
myeloproliferation, or MDS/MPN overlap. Consistent with this DNMT3A mutations are heterozygous missense substitutions at
finding, RAS is frequently mutated in patients with MPNs and codon R882 (most frequently R882H); the remainder are deletions,
CMML. frameshifts, and missense substitutions throughout the open reading
frame.
Mutations in ten-eleven-translocation 2 (TET2), have been identi-
Transcription Factors fied in 10% to 30% of patients with AML, and are enriched in patients
with prior MDS or MPN. Members of the TET gene family include
In addition to their frequent identification in novel fusion proteins, TET1 and TET2; TET1 is also rearranged in t(10;11)(p12;q23).
transcription factors are also recurrently mutated in AML. RUNX1 TET2 converts 5-methylcytosine to 5-hydroxymethylcytosine, an
mutations occur in approximately 5% to 15% of all patients with initial step in the reversion to unmethylated cytosine. Hydroxylation
AML, but are slightly more common in patients with intermediate- of methylated CpG-rich regions by TET2 activates gene programs
risk AML, particularly in association with trisomy 8 or trisomy important for cellular differentiation, including the homeobox A
13. Approximately 80% of RUNX1 mutations are located in a cluster. By contrast, TET2 loss-of-function mutations are associ-
DNA-binding domain that is homologous to the Drosophila runt ated with impaired differentiation. Mice harboring a TET2 null
protein. C-terminal domains of RUNX1 are involved in nuclear allele display enhanced stem cell self-renewal and develop myeloid
matrix localization and recruitment of transcriptional trans-activating malignancies with underlying features consistent with CMML or
and repressing factors. Overexpression of mutant RUNX1 in mice MDS. TET2 mutations do not have a consistent impact on AML
causes AML with dysplastic changes, and, in combination with EVI1 prognosis in multivariate analysis.
mutations, results in a more rapid AML phenotype. Mutations in IDH1 or IDH2 are also involved in TET deregula-
CEBPA is mutated in almost 10% of AML cases; these mutations tion via the oncometabolite 2-hydroxyglutarate (2-HG). IDH1 is
are enriched in younger patients and patients with otherwise normal primarily cytosolic, while IDH2 localizes to mitochondria. These
cytogenetics. CEBPA encodes the CCAAT/enhancer binding protein- proteins normally decarboxylate isocitrate to form α-ketoglutarate
alpha, a basic leucine zipper transcription factor. Patients with CEBPA via the reduced form of NADPH, a key reaction in the Krebs cycle.
mutations most often have normal cytogenetics; mutations result in Mutational hotspots include codon R132 in IDH1 and codons R140
loss of function and typically arise in the transactivation domain or or R172 in IDH2. IDH1/2 mutations are found in approximately
in the basic leucine zipper domain. Favorable prognosis is restricted 5% to 10% and 15% to 20% of patients with AML, respectively.
to cases with biallelic CEBPA mutations, which is associated with a The mutations are enriched in cases with a normal karyotype
distinct gene expression signature. When biallelic mutations were and frequently co-occur with NPM1 mutations. Mutant IDH1/2
engineered in a mouse model, hematopoietic differentiation was catalyzes the conversion of α-ketoglutarate to 2-HG, which sup-
impaired, but cooperating mutations were required for AML trans- presses TET2 due to competitive inhibition at the α-ketoglutarate
formation, such as the addition of FLT3-ITD. binding site. Through this mechanism, excess 2-HG results in a
DNA hypermethylation pattern similar to that observed in TET2-
mutated AML; however, this oncometabolite also interferes with
Tumor Suppressor Genes other α-ketoglutarate–dependent enzymes, including members of
the Jumonji-C domain-containing histone demethylases. Mouse
Mutations in tumor suppressor genes facilitate the development of models with IDH1 mutations in hematopoietic cells develop a disease
AML. Common examples include the canonical tumor suppressors phenotypically similar to human MDS.
TP53 and Wilms tumor 1 (WT1). Mutations in TP53 are found in
fewer than 10% of AML cases overall, but are enriched in patients
with AML with a complex karyotype, two-thirds of which will also Polycomb Complex
harbor a mutation in TP53. TP53 is a transcription factor that regu-
lates multiple signaling pathways in response to cellular stress, with an The polycomb complex plays a major role in silencing transcription
output that may culminate in cell cycle arrest, senescence, or apoptosis. during development; it functions in conjunction with trithorax group
Mutations occur throughout the TP53 gene, usually resulting in loss proteins, which activate transcription, to epigenetically modulate
of function; over half of cases have loss of heterozygosity at 17p. genes during embryogenesis. Recurrent mutations in polycomb
Mutations in WT1 occur in fewer than 10% of patients with complex genes or regulators have been identified in several cancers,
AML, but wild-type WT1 is frequently overexpressed. WT1 is a zinc including AML. Additional Sex Combs-Like 1 (ASXL1) is an
finger transcription factor that is required for normal development. enhancer of the trithorax and polycomb genes; it plays a critical role
Mutations may occur throughout the gene and generally predict loss in HOX gene expression during embryogenesis. Mutations in ASXL1
of function. One mechanism by which loss of WT1 may influence in AML typically occur in exon 12 and result in loss of function.
tumorigenesis appears to relate to DNA methylation; mutations in Expression of mutated ASXL1 in mice results in aberrant HOX gene
WT1 result in a DNA methylation pattern similar to that in TET2 activation, and, when conditionally deleted in hematopoietic cells,
mutated AML, apparently due to a lost interaction between WT1 results in anemia and leukopenia with multilineage myeloid dysplasia.
and wild-type TET2. In addition to loss of function, WT1 may also Acquired somatic mutations in ASXL1 occur in approximately 10%
have oncogenic effects. In a RUNX1-RUNX1T1 mouse model of to 20% of patients with AML and are enriched in those with underly-
AML, forced overexpression of WT1 resulted in more rapid progres- ing MDS.
sion to AML. ASXL2 is also involved in regulation of the polycomb repressor
complex, and mutations in ASXL2 are present in over 20% of patients
with AML harboring the RUNX1/RUNX1T1 translocation; they are
Regulators of DNA Methylation mutually exclusive with ASXL1 mutations in this group.
The nuclear receptor binding SET domain protein 1 (NSD1) gene
Methylation of cytosine residues is an important epigenetic mark that encodes a histone methyltransferase, which similarly has a role in
contributes to regulation of gene expression. Genes encoding factors normal development; germline mutations result in Sotos syndrome,
directly or indirectly involved in DNA methylation or demethylation, which is associated with a number of childhood cancers. NSD1
including TET2, DNMT3A, and isocitrate dehydrogenase-1 (IDH1) methylates H3K36 and is associated with transcriptional activation.
or IDH2, are recurrently mutated in AML. NSD1 is involved as a fusion partner in the recurrent translocation
DNMT3A encodes a de novo methyltransferase that catalyzes t(5;11)(q35;p15.5) with NUP98, seen in approximately 15% of
cytosine methylation at CpG dinucleotides. These mutations are seen pediatric AML, but less than 5% of adult AML, and is associated