Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Lal, R.
Somatic TP53 mutations characterize preleukemic stem cells in acute myeloid leukemia
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Beham-Schmid Christine
- Sill Heinz
- Zebisch Armin
- Altmetrics:
- Abstract:
- Acute myeloid leukemogenesis is a multistep process involving mutagenesis, epigenetic dysregulation and copy number alterations (CNAs). In this work we hypothesized that somatic TP53 mutations are early events of leukemogenesis. Employing a NSGS mouse model, we show that transplanted human TP53 mutated acute myeloid leukemia (AML) cells led to high engraftment rates with a predominant blast phenotype. However, differentiation into granulocytes and B-lymphocytes was also observed in the majority of mice analyzed. Importantly, the specific TP53 mutation was shown in up to 100% of engrafted cells. Investigating samples from patients with AML and somatic TP53 mutations, highly purified T-lymphocytes revealed the specific aberration in 75% of specimens. Furthermore, investigating early phases of specimens from patients with secondary or therapy-related AML showed the leukemia-specific TP53 mutation detectable in 80% of antecedent hematological disorders. In CFU-GM assays derived from sorted Lin-/CD34+/CD38-/CD99- single cells, TP53 mutations were frequently observed with a paucity of cooperating mutations (median, 1; range, 0-3). Apart from one concomitant DNMT3A mutation, all mutations developed sequentially in the TP53 mutated clone. In addition, a multitude of CNAs with a median of 37 losses and 34 gains per TP53 mutated AML sample were detected. Loss of heterozygosity at the TP53 locus in bulk leukemia but not colony cells suggested that CNAs are late leukemogenic events. Somatic TP53 mutations were associated with significantly reduced overall and relapse-free survival rates of intensively treated AML patients. Analysis of sequential AML specimens revealed the TP53 mutational load of comparable levels at diagnosis and relapsed/refractory stages. Our results indicate that in AML, somatic TP53 mutations characterize preleukemic stem cells, are initiating leukemogenic events and act as mediators of resistant disease. They extend previous data and confirm recent claims of TP53 mutated AML as a distinct disease entity.