Page 917 - Hematology_ Basic Principles and Practice ( PDFDrive )

800 Part VII Hematologic Malignancies

heterozygosity resulting in homozygous mutated allele and high TET2 proteins are necessary for the conversion of 5-methylcytosine
FLT3-ITD allelic ratio. to 5-hydromethylcytosine and play a role in demethylation processes
Intact functioning of the CCAAT/enhancer binding protein within the cell. TET2 mutations have been reported in 10% to 23%
(CEBPA) gene is essential for normal granulocytic differentiation. It of patients with AML with a normal karyotype. The impact of TET2
is a lineage-specific transcription factor that is required for the forma- mutations on the prognosis and outcome remains poorly defined.
tion of committed myeloid progenitors from multipotent progenitor DNMT3A mutations, which affect the DNA methyltransferase
cells. CEBPA execute this function by coupling the direct transcrip- enzymes and subsequent epigenetic modulation, have been described
tional activation of myeloid-specific genes with the arrest of cell in about 27% to 33% of normal karyotype AML and are associated
proliferation. CEBPA is an intronless gene whose mRNA can be with a worse OS (see earlier sections on Clonal Origin and Early
translated into two different AUG codons to give rise to two distinct Mutations). 12,13
isoforms, p42 and p30. Only the p42 isoform of CEBPA can promote Currently, a newly diagnosed patient with AML and a normal
proliferation arrest. CEBPA mutations, leading to arrest of differentia- karyotype should be checked for more common mutations such as
tion, are seen in 5% to 10% of de novo AML and in up to 15% of FLT3, NPM1, CEBPA, RUNX1, MLL-PTD, or EVI1, TET2 and
normal karyotype AML. Only mutations affecting both alleles, DNMT3A, which may have prognostic and possibly therapeutic
double mutations, confer superior survival as compared to single implications. Patients with overexpression of other single genes
mutations. Concomitant GATA1 and WT1 mutations are seen more should stay, until more data are collected, in a research setting of
often in double mutants while FLT3-ITD, NPM1, ASXL1, and clinical trials (Table 56.6).
RUNX1 are mutations more commonly associated with single muta-
tions, possibly contributing to the poorer prognosis. 11
A rare but specific subset of adult AML can be defined by the Acute Myeloid Leukemia with an Abnormal Karyotype
cytogenetically cryptic NUP98-NSD1 fusion gene that involves the
nucleoporin gene 98 (NUP98) on chromosome11p15, and the Among patients with an abnormal karyotype, 25% have balanced
nonhomeobox gene NSD1 present on chromosomal band 5q35. translocations and 27% showed unbalanced abnormalities or a
NUP98 encodes a 98-kDa protein of the nuclear pore complex, and complex karyotype.
is known to fuse with at least 21 different fusion gene partners in The pretreatment karyotype in AML constitutes an independent
chromosomal rearrangements in various hematologic malignancies. prognostic determinant for attainment of CR and risk for relapse and
NSD1 is thought to function both as a transcriptional co-activator survival. Four broad cytogenetic risk categories of AML are useful in
and a co-repressor. Among 293 pediatric and 808 adult cytogeneti- clinical practice: favorable, intermediate, unfavorable, and unknown
cally normal cases of AML the NUP98-NSD1 fusion gene has been (Figs. 56.26 and 56.27 and Table 56.7). It is important to perform
described in 16.1% of pediatric and 2.3% of adult AML cases. appropriate cytogenetic and FISH studies to establish the correct
14
Apparently NUP98-NSD1 has been shown to correlate with FLT3- cytogenetic risk category. Table 56.8 lists 72 of approximately 250
ITD, which is associated with increased blast percentages. recurrent chromosomal translocations in leukemia, including AML

t(8;21)(q22;q22) t(15;17)(q22;q22) inv(16)(p13q22)

Favorable
prognosis

ETO-AML1 PML-RARA CBFB

D8Z2 Intermediate
prognosis

del(5)(q15q35) del(7)(q31) t(6;11)(q27;q23) t(9;22)(q34;q11)

Unfavorable
prognosis

EGR1 D7S486 MLL BCR-ABL
Fig. 56.26 PROGNOSTIC CYTOGENETIC RISK CATEGORIES IN ACUTE MYELOID LEUKEMIA.
Favorable prognosis includes t(8;21) and ETO-AML1 fusion, t(15;17) and PML-RARA fusion, and inv(16)
and rearrangements of CBFB on 16q22. Trisomy 8 is associated with intermediate prognosis. Unfavorable
cytogenetic risk categories include monosomy 5/del(5q), −7/del(7q), and translocations of 11q23 and MLL,
represented here by t(6;11), and the Philadelphia chromosome.