Acute Myeloid Leukemia (AML) with 9q Aberrations Occuring within a Non-Complex Karyotype Is Highly Associated with CEBPA and NPM1 Mutations - A Joint Analysis of the German-Austrian AML Study Group (AMLSG) and Cancer and Leukemia Group B (CALGB).
Authors: Corbacioglu Andrea , Fröhling Stefan , Paschka Peter , Marcucci Guido , Anhalt Andreas , Urlbauer Katja , Krauter Jürgen , Larson Richard , Mrózek Krzysztof , Ruppert Amy S. , Ganser Arnold , Caligiuri Michael A. , Döhner Hartmut , Schlenk Richard F. , Bloomfield Clara D. , Döhner Konstanze 
Published: November 2019

Abstract
Background: In a previous study we showed that AML with deletion 9q (9q-) occurring in the context of a non-complex karyotype is associated with CEBPA loss-of-function mutations; their prevalence was 41% (Frohling et al., Genes Chromosomes Cancer2005;42:427). We hypothesized that disruption of CEBPA function and loss of a critical segment of 9q cooperate in leukemogenesis. This is consistent with the model of leukemogenesis, in which mutations from different complementation groups cooperate, e.g., CEBPA mutations, representing the class II mutation impairing differentiation, occur simultaneously with 9q- associated with loss and/or mutation of an as yet unidentified gene that confers the proliferative advantage (class I mutation). 9q- is also associated with t(8;21)/RUNX1/RUNX1T1, another class II mutation. Importantly, in initial studies screening for NPM1 mutations, a few patients (pts) with 9q- were reported to harbor NPM1 mutations.
Objective: To evaluate the incidence and clinical significance of mutations in the CEBPA and NPM1 genes in a large series of AML with 9q aberrations.
Methods: Fifty-seven pts exhibiting a 9q aberration on chromosomal banding analysis were screened for CEBPA and NPM1 mutations. Pts were classified into three groups:
those with 9q- occurring as a sole aberration or together with one additional abnormality other than t(8;21) (n=35); pts with 9q- occurring within a complex karyotype, defined as ≥3 abnormalities (n=10); and pts with 9q- secondary to t(8;21) (n=12).
Results: The frequencies of CEBPA and NPM1 mutations in group 1 were 49% and 29%, respectively. Strikingly, either a CEBPA or NPM1 mutation was identified in 27 of the 35 (77%) pts within this subgroup. CEBPA and NPM1 mutations did not occur concurrently. In contrast, only one CEBPA and no NPM1 mutations were detected in group 2; no pt in group 3 had mutations in CEBPA or NPM1. Although the number of pts is still limited, within group 1, pts with CEBPA mutations and those with NPM1 mutations had higher CR rates, 86% and 80%, respectively, than pts with wild-type CEBPA and NPM1, whose CR rate was 57%. Overall survival of 9q- pts with CEBPA mutations was significantly better than that of the remaining pts comprising those with NPM1 mutations and pts with wild-type CEBPA and NPM1 (p=0.03).
Conclusions: Abnormalities of 9q occurring in AML pts with a non-complex karyotype and without t(8;21) are highly associated with CEBPA or NPM1 gene mutations. CEBPA and NPM1 mutations are mutually exclusive, a finding that further supports the hypothesis that both CEBPA and NPM1 mutations act as class II mutations, which cooperate with a class I mutation affecting a thus far unknown gene on 9q. Currently, additional pts with 9q- are under investigation.