Clinico-genomic profiling and clonal dynamic modeling of TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia

Abstract

TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.

Keywords:

• Myelodysplastic syndrome
• acute myeloid leukemia
• TP53
• hematopoietic stem cell
• clonal dynamics
• hypomethylating agents

Disclosure statement

SAP serves on the AML Advisory Board for Bristol Myers Squibb and the Multiple Myeloma Advisory Board for Pfizer. SAP has a consultancy role with the Dedman Group, SIS International, and Adivo Associates. JC has a consultancy role with Jazz Pharmaceuticals and Amgen and is on the Advisory Board for Allovir. JMG has a consultancy role for Novartis and holds US Patent No. 9,012,215 and US Patent No. 10,222,376 (not licensed thus far and no royalties to date).

Author contributions

SAP, MRL, and JMG conceived and wrote the manuscript. QS, JC, KS, and JMG created the Leukemia registry and acquired the data for analysis. AE, JC, MR, and JMG analyzed the data and provided a critical review. LH, PM, and AWH conducted the cytogenetic and molecular assays.