Irrespective of the underlying histology, TP53 is one of the most dreaded set of alphanumeric combinations an oncologist can see on a mutation profile. Genetic variations in TP53, a tumor suppressor gene, contribute to several cancers’ pathology in humans, and we have all felt that trepidation as clinicians when it exists or appears on the genomic report. While de novo acute myeloid leukemia (AML) frequently harbors unaltered TP53, AML arising out of myelodysplastic syndrome or myeloproliferative neoplasm (MPN) commonly occurs because of, and reports acquisition of, this dreaded set of alphanumeric characters. And if that were not enough, they commonly find existential partnership with complex or high-risk cytogenetic abnormalities, resulting in chemoresistance and poor prognosis. All of this usually culminates in decimation of human survival due to this, the highest-risk disease known. This is true not just of the hematologic malignancies but also for a variety of solid tumors — an area in which we share similar emotions with our medical oncology colleagues.
The evolution of cancer (or life as a whole) is determined in the human genetic code. However, the translation of this genetic code into real functional molecules in the body, and the interaction of these molecules, really determine health and disease spectrum throughout the course of an individual’s life. The understanding of this interaction has evolved since the first description of human genome sequencing in 2001. These innovative studies have now brought us to the latest and greatest of comprehensive single-cell isolation and analysis. Single-
cell analysis allows us to examine different cell populations from the same tumor, ultimately allowing unique insights into their functions associated with the pathological processes. Multi-omics includes a comprehensive analysis of the genomic, transcriptomic, metabolomic, epigenomic, and microbiome architecture of each cell. This multi-omics analysis at tumor bulk level has the potential to provide a comprehensive understanding of cellular processes through the integration of different types of molecular data, including data on mutations, mRNAs, proteins, and metabolites. This can provide deeper insights into tumor biology and cell-type–specific gene regulation than a single type of ‘omics data alone.
So, if we combine the above two concepts, single-cell multi-omic analysis provides a unique opportunity for a deeper dive into understanding TP53. As Dr. Jyoti Nangalia stated in her introduction to this plenary abstract, the protein P53, encoded by the TP53 gene, is the “guardian of our genome”. We can learn about its likelihood to take off with the most aggressive disease when it appears, or why it’s as stubborn as it is when it comes to response to available therapeutic agents via single-cell analysis. Undoubtedly, this analysis deserves Plenary Scientific Session recognition. The abstract, titled “Single-Cell Multi-Omics Reveals the Genetic, Cellular and Molecular Landscape of TP53 Mutated Leukemic Transformation in MPN” was presented on Sunday by Dr. Alba Rodriguez-Meira (pictured), who with her co-authors from Dr Adam Mead’s laboratory, used the MPN disease model to study the biology of TP53 mutations and transformation to secondary AML. In my exclusive chat with Drs. Rodriquez-Meira and Mead, I learned that the specific multi-omics assay used in this study was developed by Dr. Rodriquez during her doctorate, and in the context of TP53, is a very powerful technique as this can tease apart intertumoral heterogeneity and allelic resolution. That means we know which cells harbor homozygous TP53 mutation and which cells are TP53 heterozygous within the same patient. They can also detect wild-type TP53 cells, which allows further understanding of their transcriptome and cell extrinsic mediators of hematopoiesis. They noted in the acute phase or blast transformation of the disease, major clonal dominance of cells that have lost TP53 wild type either via acquisition of two different point mutations (biallelic inactivation) or acquisition of a point mutation and a deletion of another copy of TP53. With this single-cell analysis, they were able to detect both types of patterns occurring in the same patient. Interestingly, even the wild-type TP53 preleukemic stem cells had high CD34+ undifferentiated cells, aberrant self-renewal, and lower differentiation capacity. Since these are TP53 wild-type (or without a TP53 mutation), this has to be extrinsically mediated. Another provocative finding from their data suggested increased interferon responses and hence, a real role of inflammatory signaling, in TP53 heterozygous cells that do progress to blast phase (versus those that stay in chronic phase for a long time). Lastly, acquisition of TP53 is quickly followed by acquisition of chromosomal abnormalities. Certain chromosomal abnormality patterns, especially chromosome 7 loss, are collectively required for leukemic stem cell expansion.
Overall, this is a cardinal addition to our understanding of TP53 pathology and the recognition that it’s not all from within the cell but rather extrinsic suppression that promotes TP53-mutant transformation, will further expand opportunities about how to shut this down early in the course or to intervene before the clone expands out of control. Since TP53 spans a wide variety of diagnoses, this study will carve the way for further understanding of other malignant processes.
Dr. Jain indicated no relevant conflicts of interest.
