Impact of 9q Deletions on the Classification in AML (2024)

Background: In the 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia the deletion of the long arm of chromosome 9 (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.

Aim: Investigation of the frequency of del(9q) in AML and its accompanying molecular and cytogenetic abnormalities to assess whether or not del(9q) is associated with a myelodysplasia-related mutation profile.

Patients and Methods: We evaluated 9762 AML patients (pts) diagnosed between 2005 and 2017 for del(9q) using chromosome banding analysis (CBA). Pts with del(9q) were further analyzed for mutations in NPM1 , CEBPA and RUNX1 with amplicon sequencing to categorize them according to the WHO classification. Pts without a class defining aberration or a complex aberrant karyotype were screened for AML- or MDS-related mutations ( ASXL1, BCOR, EZH2, FLT3- ITD , FLT3- TKD , SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2 ). Variants of unknown significance were excluded from statistical analysis. The size of the deleted region on chromosome 9 was evaluated by array CGH (Agilent Technologies, Santa Clara, CA) and NUP98 -rearrangements were investigated by FISH(MetaSystems, Altlussheim, Germany).

Results: In 114/9762 pts (1 %) a del(9q) was detected by CBA. This cohort with del(9q) comprised 60 male and 54 female pts, median age was 63 years (range: 16 - 90 years). Del(9q) was accompanied by the following rearrangements: RUNX1-RUNX1T1 rearrangement in 20/114 pts (18 %), PML-RARA in 5/114 pts (4 %), KMT2A in 2/114 pts (2 %) and MECOM in 1/114 pts (1 %). In 20/114 pts (18 %) a NPM1 mutation and in 7/114 pts (6 %) a biallelic CEBPA mutation was observed. Furthermore, RUNX1 mutations were found in 3/114 pts (3 %). The remaining 56 pts (49 %) were divided into the following three groups: pts with del(9q) as a sole cytogenetic abnormality (del(9q) sole, 8/114 pts, 7 %), pts with one or two additional cytogenetic aberrations (del(9q) other, 19/114 pts, 17 %) and pts with complex aberrant karyotype (complex, 29/114 pts, 20 %) harboring 4 to 29 cytogenetic aberrations (median: 8). Cases with del(9q) sole and other (n = 27) were further characterized. NUP98 -FISH analysis revealed a NUP98 -rearrangement in 5/27 pts (19 %) in the del(9q) sole and other group. Moreover, two pts with del(9q) showed AML specific rearrangements (t(8;16)(p11;p13) and t(3;5)(q25;q35)). The most frequently mutated genes in del(9q) sole and other were: FLT3 -ITD (8/23 pts, 35 %), TET2 (7/27 pts, 26 %), FLT3 -TKD (4/21 pts, 19 %) and WT1 (3/26 pts, 11 %). A very high frequency of FLT3 -ITD and FLT3 -TKD were found in pts with del(9q) and balanced rearrangements (5/7 pts, 71 %).

To identify whether pts with del(9q) sole and other rather resemble a molecular mutation profile typical for secondary AML arising from MDS (s-AML), the presence of gene mutations related to s-AML (according to Lindsley, et al., 2015, Blood) was evaluated. 9 pts (33 %) had a mutation in at least one of these genes, 14 pts (52 %) showed no such mutation and 4 pts (15 %) could not be fully analyzed.

Array CGH showed that in pts with del(9q) sole the deletion size ranged from 14 - 42 Mb (median: 28 Mb), in pts with del(9q) other from 19 - 70 Mb (median: 32 Mb). A minimal deleted region for pts with del(9q) sole and other could not be determined for all pts due to the strong variation between the respective deleted regions.

Follow up data was available for 75 pts with a median follow-up of 27 months. The median overall survival (OS) for pts with RUNX1-RUNX1T1 , NPM1 and bialleic CEBPA mutation was not reached. It was 73 month for pts with del(9q) sole and other and 16 month for pts with complex karyotype, RUNX1 mutations or MECOM rearrangements. The OS of first two groups did not differ significantly, but was significantly distinct from the last group (p = 0.03 and 0.03, respectively).

Conclusion: In 1 % of AML pts a del(9q) was present. Del(9) frequently co-occured with RUNX1-RUNX1T1 , biallelic CEBPA and NPM1 mutations, NUP98 -rearrangements and other AML-typical translocations. A mutation signature typical for s-AML was infrequent. Thus, it seems reasonable that the del(9q) is no longer regarded as a defining cytogenetic abnormality for AML with myelodysplasia-related changes, in particular as prognosis in del(9q) cases with non-complex karyotype is favorable.