Single-cell multi-omic analysis provides insight into the course of malignancies mediated by TP53

In a plenary summary at the ASH 2021 annual meeting, Alba Rodriguez-Meira, PhD-c, of the MRC Weatherall Institute of Molecular Medicine at the University of Oxford in the UK, described a new multi-analysis single-cell omics of, cellular and molecular landscape of TP53– controlled transformation. The tool can provide unique insight into the progression of chronic hematologic malignancies to acute aggressive leukemia.

TP53 is the most commonly mutated gene in human cancer. Presence of “multi-hit” TP53 mutations is associated with a lack of response to conventional treatments and poor outcomes, the authors explained.

To better understand the biological basis of TP53-Mutant-induced clonal evolution, Ms. Rodriguez-Meira and colleagues studied this process in a model of myeloproliferative neoplasm (MPN). This model is ideal because progression to secondary acute myeloid leukemia (AML) frequently occurs through the acquisition of TP53 missense mutations, they noted.

Then, to characterize tumor phylogeny, cell hierarchies and molecular characteristics of TP53The transformation led by Ms. Rodriguez-Meira and colleagues performed a single-cell multi-omic TARGET-seq analysis of 22,116 hematopoietic stem and progenitor cells (HPSCs) from 35 donors and 40 temporal controls. They identified a convergent clonal evolution leading to a complete loss of TP53 wild type alleles during transformation, including parallel evolution of TP53 multi-hit subclones in the same patient and JAK2-negative development.

All patients had a complex clonal course caused by chromosomal abnormalities. In addition, TP53 According to Ms. Rodriguez-Meira, multi-stroke HSPCs without chromosomal abnormalities have been observed rarely. Subclones with recurrent abnormalities such as monosomy 7 showed upregulation of transcription associated with RAS and preferentially extended in xenograft models.

These data indicated that TP53 missense mutation, loss of TP53 the wild-type allele and cytogenetic evolution are all necessary for the expansion of leukemic stem cells.

In addition, the researchers performed an integrated transcriptomic analysis of secondary AML samples. This revealed three main populations:

  • a TP53-clusters of mutants characterized by an erythroid signature
  • a leukemic stem cell TP53-cluster of mutants
  • a TP53-wild-type preleukemic cluster

Ms. Rodriguez-Meira said that the TP53-the group of mutants characterized by an erythroid signature was an unexpected finding since there were no cases with diagnostic features of erythroid leukemia.

The researchers then derived a leukemia stem cell score of 48 genes from the leukemia stem cell group. This score had a prognostic impact in an independent AML cohort (hazard ratio = 3.13). Ms. Rodriguez-Meira said the score was predictive of the outcome regardless of TP53 status for both de novo and secondary AML, “demonstrating its wider potential clinical utility”.

TARGET-seq also enabled researchers to characterize the TP53 wild type preleukemic cells, which were found almost exclusively in the HSC compartment of the immunophenotypic line (CD34 + CD38-CD90 + CD45RA-). These preleukemic cells from secondary AML samples showed increased stem, increased quiescence, aberrant inflammatory signaling, and defective differentiation compared to HSCs from control donors or donors with MPN. Ms Rodriguez-Meira said these results indicate “extrinsic suppression of residual cells TP53 wild type hematopoiesis’.

Finally, the longitudinal analysis of TP53-heterozygous mutant HSPCs at different stages of development showed aberrant inflammatory signaling in the genetic ancestors of the multi-hit leukemia stem cell TP53, but not the presence of TP53 mutants alone, was predictive of further transformation.

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