Subclonal TP53 mutations in acute myeloid leukemia

Results of the research proposed will provide novel insights into the complex biology of acute myeloid leukemia (AML) and define a potential novel biomarker for this disease. Acute myeloid leukemia (AML) is an aggressive, heterogeneous neoplastic disorder resulting from gene mutations and epigenetic dysregulation. Based on the heterogeneity of AML, personalized medicine approaches for diagnostic and prognostic purposes as well as tailored treatment strategies have been introduced into clinical practice. A characteristic biological feature of AML is the coexistence of several different malignant cell populations clones - derived from mutated hematopoietic stem cells. Here, we will investigate the role of subclonal TP53 mutations as a novel biomarker in AML and elaborate their biological characteristics. Mutations in the tumor suppressor gene TP53 are found in up to 20% of AMLs, define a distinct AML subtype and are associated with an extremely adverse prognosis. We have recently shown that TP53 mutations are initial events of acute myeloid leukemogenesis affecting preleukemic stem cells. In a first part of the project, we will analyze large, prospectively treated AML cohorts for the clinical significance of subclonal TP53 mutations in cooperation with the German-Austrian AML study group (AMLSG). We will, thereby, employ ultrasensitive next-generation sequencing techniques allowing the detection of subclones as small as 0.1%. Next, we will prove whether small TP53 mutated clones exhibit leukemia stem cell properties using a novel humanized ossicle mouse model that allows the detection of such clones with improved sensitivities. Furthermore, we will establish clonogenic assays to investigate the clonal architecture of AMLs with small TP53 mutations incorporating the assessment of cooperating mutations in other genes. TP53 is the most frequent gene in human malignancies. The results obtained within this project will, therefore, also be of importance for other fields in hematology and oncology.

TP53 mutations are constant aberrations in patients with acute myeloid leukemia (AML). They are associated with characteristic biological features of leukemic cells and an adverse outcome. In this research project, we investigated the role of subclonal TP53 mutations in AML that affect only a smaller percentage of leukemic cells. In a humanized mouse model, we transplanted samples of AML patients showing subclonal TP53 mutations. They were able to engraft and differentiate into myeloid as well as lymphoid cells indicating affection of preleukemic stem cells. In the clinical part of the project, we investigated more than 1.500 AML patients treated intensively within study protocols. As was shown for clonal TP53 mutations, subclonal ones were also associated with therapeutic resistance and inferior survival. These data have implications for classification as well as risk stratification of patients with AML.