AML patients with CEBPα mutations mostly retain identical mutant patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples

Abstract

The roles of CEBPalpha mutations and its cooperating mutations in the relapse of acute myeloid leukemia (AML) are not clear. CEBPalpha mutations were analyzed on 149 patients with de novo AML at both diagnosis and relapse. Twenty-two patients (14.8%) had the mutations at diagnosis, two patients had N-terminal nonsense mutations alone, one had homozygous inframe duplication at the bZIP domain, and 19 patients had both N-terminal and bZIP mutations. Twenty patients relapsed with identical mutant patterns, two lost CEBPalpha mutations and none acquired the mutations at relapse. Cloning analysis showed that the N-terminal and C-terminal mutations occurred on separate cloned alleles and also on the same alleles in most of the diagnosis and relapse samples. Losing one of the two or more mutations on the same allele or acquiring the other mutation on the allele original carrying single mutation were observed not infrequently in the paired samples analyzed. Seven patients with CEBPalpha mutations had cooperating mutations with FLT3/ITD, FLT3/TKD or N-ras but not K-ras mutations. Our study showed that 91% of de novo AML harboring CEBPalpha mutations at diagnosis retained the identical mutant patterns but frequently changed in the allelic distribution at relapse.

CCAAT/enhancer binding protein‐alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes

“…We identified 3 types of polymorphisms including nt1175_ 1180dup, nt1281G>T and nt1401C>T. The nt1175_1180dup and nt1281G>T polymorphisms had been reported in previous studies [16][17][18][19] whereas nt1401C>T is a novel polymorphism. The most common type of polymorphism was the nt1175_1180dup which led to a histidine-proline duplication in the TAD2 domain.…”

“…1 Previously reported mutations or polymorphisms. [15][16][17][18][19] were also found in M4 (25%), M2 (22.8%), M3 (21.8%), M1 (20.8%) and M0 (14.3%), respectively. One out of 2 M6 patients also had the CEBPA polymorphism.…”

“…Valk et al 25 17/285 (6) Asia Taiwan Lin et al 16 16/104 (15) Lin et al 26 13/99 (13) Shih et al 17 22/149 (14.8) Thailand…”

“…12,[16][17][18][19][20][21][22][23][24][25][26] In this study, CEBPA mutations were found in 34 cases of 247 cases (13.8%) of Southeast Asian AML, the frequency of which was comparable to that of Taiwan (13-15%), 16,17,26 Germany (14%), 18,21,22 Switzerland (17.9%) 23 and France (11%), 24 but was slightly higher than that of the Czech Republic (9.2%), 18 the United States (7.3%) 12 and The Netherlands (6%). 25 Our study represents the first series reported from the ethnically distinct Southeast Asian region and is one of the largest series ever reported with respect to the CEBPA polymorphisms and mutations.…”

Transcriptional dysregulation during myeloid transformation in AML

“…Eleven groups now have reported the presence of genomic CEBPA mutations in AML patients, with the frequency varying between 5 and 14% (Pabst et al, 2001b;Gombart et al, 2002;Preudhomme et al, 2002;Barjesteh van Waalwijk van Doorn-Khosrovani et al, 2003;Snaddon et al, 2003;Frohling et al, 2004Frohling et al, , 2005Bienz et al, 2005;Lin et al, 2005;Smith et al, 2005;Shih et al, 2006). The mutations can be largely divided into two types (Figure 1): First, N-terminal frameshift mutations result in premature termination of the fulllength 42 kDa form of the CEBPA protein, while preserving the 30 kDa form initiated further downstream (Pabst et al, 2001b).…”