University of Texas MD Anderson Cancer Center researchers have started to explore the clonal diversity and the advancement of acute myeloid leukemia.
Clonal diversity is increasingly studied and understood to have central importance as a key characteristic of cancer. Changes in the specific genetic makeup of precancerous and cancer cells change via mutations as tumors progress. A given change or mutation can impart a survival advantage and lead to subsequent cells with this advantage. Research has uncovered that this phenomenon may be associated with poor prognoses, treatment resistance, and recurrence. Understanding and defining specific cancer developmental history could provide information that would be useful to support personalized medicine efforts for patients with cancer.
Scientists from the University of Texas MD Anderson Cancer Center investigated the clonal diversity and evolution of acute myeloid leukemia (AML) via single-cell sequencing. The approach is a next-generation sequencing method used to analyze genetic information in order to uncover information otherwise obscured with traditional profiling methods that analyze bulk cell populations. The researchers surveyed 154 bone marrow mononuclear cell samples collected from over 100 patients with AML. The data showed mutations that co-occur and those that were mutually exclusive.
The most common mutations observed were NPM1, DNMT3A, and NRAS. NPM1 mutations were strongly associated with decreased expression of CD34 cells (hematopoietic progenitor cell antigen), while TP53 mutations were associated with higher CD34 expression. Interestingly, researchers found that TET2-U2AF1-DNMT3A (triple mutant cells) are associated with the CD34, CD117 (hematopoietic stem cell markers), and TET2-U2AF1-DNMT3A-NRAS (quadruple mutant cells) had the CD33, CD34, and CD38 (myeloblastic phenotype). Linear clonal evolution (classical model) was predominant in half of the patients with AML. The rest had branching clonal evolution, in which clones diverge from a common ancestor and evolve, resulting in various lineages.
With the single-cell sequencing data at hand, the researchers could see how the clonal makeup changed in response to anti-cancer therapies. For example, a patient treated with azacitidine, an FLT3 inhibitor, had a subclone with an FLT3 mutation associated with AML relapse. The study data demonstrated the role of clonal expansion in cancer progression and treatment resistance and may allow predictive measures regarding treatments that may have the most likely positive outcomes.
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Single-Cell Sequencing Reveals Clonal Diversity Among AML Patients. (2020). Retrieved 14 December 2020, from https://www.genomeweb.com/sequencing/single-cell-sequencing-reveals-clonal-diversity-among-aml-patients#.X9fvx6pKhUN