Role of the transcription factors gata2 and myb in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) refers to a heterogeneous group of clonal hematopoietic malignancies that predominantly affect middle-aged and elderly adults. Heterogeneity of AML results from a complex network of cytogenetic and molecular aberrations. Major progresses have been made in our understanding of the molecular basis of AML; however, advances in the pathophysiology of AML have not yet lead to major improvements in overall survival of adults with this disease. To date, karyotype at diagnosis provides the most important prognostic information for patients with AML, and recurrent structural and numeric cytogenetic aberrations have been identified as diagnostic markers as well as independent prognostic factors. Nevertheless, more than 40% of cases have a normal karyotype. Patients with normal cytogenetics show an intermediate response to therapy and a remarkable heterogeneity of genetic mutations at the molecular level. Consequently, it is important to identify molecular markers in this subgroup of patients, which allowed further classification and prognostic predictions, and could be candidates for molecularly targeted therapies. As the hallmark of AML is a severe block in myeloid differentiation, aberrations that affect the activity of key transcription factors in hematopoiesis are particularly important. We hypothesized that the transcription factors GATA2 and MYB could have a relevant role in the transformation of AML. Our aim was to study the prevalence and prognostic significance of GATA2 and MYB in AML, their mechanisms of overexpression, and their role in the leukemic transformation of patients with AML. Our results show that high expression of MYB characterizes a subset of patients with normal karyotype, and it is involved in the activation of pathways responsible of the transformation of myeloid leukemia. Furthermore, the synergistic effect of combined treatments with MYB knockdown, suggests that MYB could be a new target for therapy in patients with AML and high MYB expression. We also demonstrated that GATA2 overexpression is a recurrent event associated with poor outcome in AML. Interestingly, GATA2 high levels positively correlated with WT1 overexpression, enabling to distinguish a group with worse prognosis in these cases. GATA2 overexpression was also associated with FLT3-ITD and NPM1 mutations in patients with normal karyotype, suggesting that might be a cooperative event in the leukemic transformation of AML. Our data indicate that GATA2 overexpression could be a useful molecular marker predictive of poor clinical outcome in AML. Finally, our preliminary results show that the GATA2 transcription factor might regulate MYB expression in acute myeloid leukemia, and that GATA2 and MYB high expression might cooperate in the leukemic transformation of AML.