P052 | THE PRESENCE OF TP53 VARIANTS REGARDLESS OF CO-MUTATIONAL PROFILE AFFECTS PROGNOSIS AND MODULATES WT1 TRANSCRIPTIONAL ACTIVITY IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

A multicenter cohort of 59 patients with AML or MDS/AML harboring TP53 mutations, irrespective of variant allele frequency (VAF), was collected. Thirty-five patients had de novo AML (59.3%), 14 secondary AML (23.7%), 6 therapy-related AML (10.2%), and 4 MDS/AML (6.8%). The median age at diagnosis was 72 (32-88). Most patients (23, 40.4%) were treated frontline with intensive therapies. About one third received hypomethylating agents (HMA) plus venetoclax, 15.8% HMA alone and 10.5% supportive care. Half of cases reached complete response (CR or iCR), 4 (12.5%) partial response and 11 (34.4%) were refractory. The median OS was 7.3 months. Most patients had biallelic TP53 alterations (84.2%), single TP53 mutation (81.4%) and complex karyotype (77.1%). About half of cases harbored additional mutations in other myeloid-related genes, mainly DTA genes (18.6%), IDH1 and IDH2 (10.2% and 5.1%), and RAS pathway genes (8.5%). Co-mutations were more frequent in cases with monoallelic TP53 configuration (p=0.035). TP53 mutations were mainly missense variants (79.3%), with all frameshift variants clustering in cases with biallelic configuration (p=0.003). Non-functional transcriptional activity and dominant-negative effect were defined for more than 90% of TP53 mutations and 22 variants (37.3%) were localized in hotspot sites. De novo AML or therapy-related AML (94.3% and 83.3%) mainly showed a single TP53 mutation, while multiple mutations were more frequent in sAML and MDS/AML (p=0.008). The clinical outcome of TP53-mutated AML patients was dismal regardless of TP53 allelic status, co-mutations, complex karyotype or different VAF ranges. However, the presence of hotspot mutations or deletion/monosomy 7 characterized patients with worse OS (p=0.007). Lastly, we observed a high expression level of Wilms tumor 1 gene (WT1) in TP53-mutated AML as compared to other ICC- and WHO-defined subsets, and a positive correlation with TP53 VAF (p=0.03). Comparing the expression levels of WT1-targeted genes LEF1 (up-regulated) and CXCR4 (down-regulated), we observed that LEF1 was reduced while CXCR4 was significantly increased (p<0.001) in both TP53-mutated and WT1-mutated AML subsets. Our findings confirm the poor prognosis of TP53-mutated AML irrespective of co-mutations or TP53 allelic status. Hotspot mutations or deletion/monosomy 7 seem to define a subset of cases with worse outcome. Our data also suggest that TP53 dysfunction may influence WT1 transcriptional activity.