The Implication of TP53 Allelic Status for Outcome and Erythropoiesis in MDS

Background: TP53 allelic status and size of TP53 mutants (TP53^MT) clone were critical for diagnostic and prognostic precision in myelodysplastic syndromes (MDS). Based on these findings, most recent myeloid tumors classification formally proposed the new subtype of MDS with TP53^MT. However, recent data were conflicting regarding the prognostic impact of TP53 allelic status.

Aims: To evaluate the prognostic impact and clinical characteristics of allelic status and clone size of TP53^MT in MDS.

Methods: 195 TP53 mutant patients from 1436 (13.6%) newly diagnosed patients detected by next-generation sequencing (NGS) were included. In addition of TP53 VAF and canonical karyotyping and FISH, we performed TP53 copy number assay through Multiplex Ligation-dependent Probe Amplification (MLPA) and NGS to more precisely determine the TP53 allelic status.

Results: 195 patients with TP53^MT were classified into mono/multi-hit (34.4% and 65.6%) subgroup based on the 2022 ICC classification. Of note, in disagreement with prior studies, our survival analysis indicated that patients with mono-hit had much shorter survival than patients without TP53^MT and complex karyotype (CK) (mOS: 30 months vs. 77 months, P=0.001) and superior survival than patients with multi-hit (mOS: 9 months, P<0.001). Patients without TP53^MT, but with CK had similar outcome (mOS: 48 months) as mono-hit and patients without TP53^MT and CK, but with -17/17p- had similarly dismal survival (mOS: 13 months) as multi-hit. We also assessed TP53 allelic status in predicting the outcome in subgroups classified by age and percentage of blasts in bone marrow (BM). Of note, mono TP53^MT indicated an inferior outcome relative to TP53^WT without CK in patients with< 65-year or < 5% blasts, but the prognostic impact of mono-hit was not significant in patients with>65-year or > 5% blasts. OS analysis based on 2022 WHO classification showed the same trend as mentioned above (data not shown). To further characterize the association between TP53 allelic status in single cell and outcome, we selected 6 patients and applied single-cell mutational analysis in CD34+ BM cells. We found that dismal outcome associated with the frequency of biallelic lesions in CD34+ cells, even though bulk NGS showed micro TP53 clone size. For example, in a MDS-U case (2022 ICC/WHO subtype: MDS, NOS-SLD/MDS-biTP53) with only 6-month survival after diagnosis, the bulk NGS showed two TP53^MT (R273H with a VAF of 4.8% and R278H with a VAF of 2.1%) and both FISH and CNA did not showed copy number alteration. However, 95% of the CD34+ cells were biallelic inactivation (R278H/R278H and R273H/R278H). We also assessed the association between TP53^MT and clinical characteristics. Interestingly, the percentage of erythroid progenitors was significantly higher in patients with multi-hit TP53MT and Y220 missense mutations accompanied with lower EPO level and smaller size of matured red cell.

Summary: In sum, our findings emphasized the prognostic implication of mono-hit TP53 mutations. Moreover, our data indicated that mutant TP53 driven-neoplastic dyserythropoiesis was different to classical erythroid lineage dysplasia in MDS.

No relevant conflicts of interest to declare.