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

TABLE 88–2. Commonly Mutated Genes In Cytogenetically Normal Acute Myelogenous Leukemia
Approximate
Frequency in AML
with Normal
Mutated Gene Karyotype (%) Implication Comments References
NPM1 50 More-favorable outcomes Most frequently mutated gene in AML. 124–129
Allogenic transplantation not needed in first
remission if this mutation occurs in absence
of mutated FLT3-ITD
FLT3 ITD 40 Less-favorable outcomes 124, 125, 130–137
DNMT3A 20 Less-favorable outcomes Seen more often in AML patients with nor- 137–143
mal cytogenetics. Mutant NPM1, FLT3-ITD,
and IDH1 have been found more frequently
in AML patients with DNMT3A mutations
compared to those with wild-type DNMT3A
RUNX1 15 Less-favorable outcomes 144–149
TET2 15 Less-favorable outcomes Coincidence of mutated TET2 with NPM1 150–153
mutation in the absence of FLT3-ITD muta-
tion predicts a less-favorable outcome
CEBPA 15 More-favorable outcomes Only cases with double mutations associ- 124, 154–157
ated with favorable outcomes
NRAS 10 Little effect on prognosis 144
IDH1 or IDH2 10 Little effect on outcomes More frequent in AML patients with normal 138, 158, 159–164
cytogenetics. Frequently associated with
NPM1. Adverse prognostic factor if present
with mutated NPM1 without FLT3-ITD. Serum
2-hydroxyglutarate levels indicate high
probability of IDH mutation
MLL-PTD 8 Less-favorable outcomes 144
WT1 6 Less-favorable outcomes More frequent in females than in males (6.6 166, 167
vs. 4.7%; P = 0.014) and in patients <60 than
in patients >60 years (P <0.001)
FLT3-TKD 6 Little effect on outcomes May appear after use of FLT3-ITD inhibitor 132, 136

Gene frequencies are approximations with some variation from study to study. Outcome statement does not reflect effect of interacting muta-
tions unless otherwise noted in comments. Outcome statements are based on consensus and vary from one study to another.
AML, acute myelogenous leukemia; CEPBα, CCAAT/enhancer binding protein alpha; DNMT3A, DNA methyltransferase 3A; FLT, FMS-like tyrosine
kinase; IDH, isocitrate dehydrogenase; ITD, internal tandem duplication; MLL, myeloid-lymphoid (mixed-lineage) leukemia; NPM, nucleophos-
min; PTD, partial tandem deletion; RAS, rat sarcoma; RUNX, Runt-related transcription factor; TET, ten-eleven translocation; TKD, tyrosine kinase
domain; WT, Wilms tumor.

cytogenetic patterns. These cases more frequently had mutations in favorable impact in such cases. Another series found RUNX1 muta-
138
147
NPM1, FLT3, and IDH1 genes as well. DNMT3A mutations are asso- tions to be twice as common in older than younger patients with normal
139
ciated with a poorer prognosis 139–142 and their significance appears to be cytogenetics, and to have an adverse outcome effect in both age groups.
age-dependent. The R882 mutation was associated with adverse prog- Mutated blasts had molecular signatures suggesting origin in a primitive
143
nosis in older patients, and non-R882 mutations with adverse prognosis hematopoietic cell. RUNX1 mutations have been found to cooperate
148
in younger patients. with granulocyte colony-stimulating factor receptor (CSFR) mutations
RUNX1 Mutations The RUNX1 gene is located on chromosome in congenital neutropenia to lead to acute leukemia or MDS. 149
21q22 and is involved in hematopoiesis at all stages through its interac- TET2 Mutations The TET2 protein inactivation may occur
tion with CBFβ. It acts as an activator or repressor of numerous genes, through a loss of function mutation, deletion, or through IDH1/2 muta-
including transcription factors. 144,145 In de novo AML, RUNX1 mutations tions. It is a member of a family of dioxygenases that catalyze conversion
were found with normal and noncomplex karyotypes. They were some- of 5-methyl-cytosine to 5-hydroxymethyl-cytosine and promote DNA
times associated with MLL-PTD (partial tandem duplication [PTD]) demethylation. TET2 has many roles in normal hematopoiesis, and
and FLT3-ITD, and they were associated with a poor prognosis inde- knockout mice show that it is a tumor suppressor, which haploinsuffi-
pendent of other molecular mutations. Another group found these ciency initiates myeloid transformations. TET2 mutations are found
146
150
mutations in 5.6 percent of cases, associated with cytogenetically nor- in approximately 25 percent of patients and in those who have mutated
mal AML and an association with MLL-PTD mutations, refractory dis- CEBPα and/or mutated NPM1 without a FLT3/ITD mutation. 151,152
ease, and, as an independent risk factor, an inferior relapse-free survival Patients with AML and a TET2 mutation had a shorter event-free and
and overall survival. The use of allogeneic HSC transplant did have a overall survival compared with patients who were TET2 wild-type. They

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