Mechanisms behind TP53 mutations revealed in myeloproliferative neoplasms

A single-cell, multi-omics analysis into the mechanisms behind TP53-mediated transformation of haematological malignancies towards acute leukaemia revealed novel aspects of the genetic, cellular, and molecular changes that occur during this transformation. Since TP53 mutations are common, these results may have relevance for other cancer types [1].

Multi-hit TP53 mutations are associated with treatment resistance and a worse prognosis in myeloid malignancies. Therefore, Dr Alba Rodriguez-Meira (University of Oxford, UK) and colleagues aimed to unravel the biological basis of TP53-mediated transformation of haematological malignancies. Since myeloproliferative neoplasms (MPN) frequently progress towards secondary acute myeloid leukaemia (AML) due to TP53 missense mutations, the team performed single-cell, multi-omic TARGET-seq analysis of haematopoietic stem and progenitor cells (HSPCs) (n=22,116) in 26 patients with MPN in different stages of the disease, at 40 timepoints. In addition, 9 healthy controls were included in the analysis.

The clonal evolution during the transformational process of the disease was characterised by a loss of TP53 wildtype alleles and the evolution of TP53 multi-hit subclones. Moreover, TP53 multi-hit HSPCs were driven by chromosomal abnormalities. These results indicate that cytogenetic evolution, loss of TP53 wildtype alleles, and TP53 missense mutations are collectively responsible for leukaemic stem cell (LSC) expansion.

Three major TP53-mutant clusters were identified, displaying an erythroid signature, an LSC signature, and a haematopoietic stem cell (HSC) signature, respectively. Notably, the authors detected dysregulation of key stem cell regulators in the LSC cluster, from which they developed a 48-gene LSC score. A high LSC score was predictive of a worse survival probability (HR 3.13), regardless of TP53 status or disease stage, indicating a broader clinical applicability.

Furthermore, the authors identified TP53 wildtype pre-leukaemic cells in the HSC compartment. The observed increased stemness and quiescence, abnormal inflammatory signalling, and differentiation defects of these cells, compared with MPN and control participants, suggests that cell-extrinsic haematopoietic suppression of residual TP53 wildtype is a distinctive process in disease transformation.

Finally, the authors showed that, next to the presence of TP53 mutations, abnormal inflammatory signalling in the genetic ancestors of TP53 multi-hit LSCs was predictive of disease transformation: pro-inflammatory stimuli were associated with a 3-fold competitive advantage of TP53-mutant cells.

1. Rodriguez-Meira A, et al. Single-Cell Multi-Omics Reveals the Genetic, Cellular and Molecular Landscape of TP53 Mutated Leukemic Transformation in MPN. Abstract 3, ASH 2021 Annual Meeting, 11–14 December.

 

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Posted on 4 February 2022