Impact of 9q deletions on the classification of patients with acute myeloid leukemia

Excerpt

Deletions in the long arm of chromosome 9, del(9q), are recurrent but rare cytogenetic aberrations in myeloid neoplasms including acute myeloid leukemia (AML), where they were observed with a frequency of ~ 2% (Langabeer et al. 1998; Grimwade et al. 2010; Naarmann-de Vries IS et al. 2018). Del(9q) is considered as marker of intermediate risk according to the MRC classification (Grimwade et al. 2010; Döhner et al. 2010, Grimwade et al. 2016). Cytogenetically, del(9q) can be observed as a sole abnormality or in association with other cytogenetic aberrations. In more detail, a significant association with t(8;21)(q22;q22) (RUNX1-RUNX1T1 rearrangement) and t(15;17)(q24;q21) (PML-RARA rearrangement) was described (Langabeer et al. 1998; Döhner et al. 2010). Moreover, AML with del(9q) was characterized by frequent mutations of NPM1, DNMT3A, CEBPA and WT1, and mutations affecting NPM1 and DNMT3A were exclusively identified in patients with del(9q) as the sole abnormality (Fröhling et al. 2005; Herold et al. 2017). A minimally deleted region of del(9q) was detected in patients with AML that comprises seven genes potentially involved in leukemogenesis (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2). Expression of these genes was found to be significantly reduced in patients with del(9q) compared to AML patients with normal karyotype (Naarmann-de Vries IS et al. 2018). Moreover, two genes closely related to the commonly deleted region of del(9q) (TLE1 and TLE4) were identified to contribute to leukemogenesis due to haploinsufficiency in patients with t(8;21)(q22;q22) (Dayyani et al. 2008). In the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, del(9q) was excluded as a defining cytogenetic abnormality for AML with myelodysplasia-related changes due to its frequent association with NPM1 and biallelic CEBPA mutations, which themselves define AML subgroups (Arber et al. 2016). Thus, the aim of the present project was the investigation of the frequency of del(9q) in AML and its accompanying molecular and cytogenetic abnormalities and assessment whether or not del(9q) is associated with a myelodysplasia-related mutation profile. …