Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms

Abstract

Acute leukemias comprise a group of hematological malignancies characterized by the expansion of blasts in bone marrow and peripheral blood, which is mainly due to the loss of differentiation ability of stem cells to functional cells in terminal stage, deregulation of proliferation and resistance to apoptosis. The mortality of adult patients with acute leukemia is very high, making it imperative to identify new molecular markers and signaling pathways that may be useful in prognostic definition, therapeutic response and the development of new treatment options. Stathmin 1 is a microtubule destabilizing protein that includes multiple signaling pathways and has been described as potentially regulated by oncogenes associated with hematological malignancies, including JAK2V617F, PML-RAR± and BCR-ABL1. In addition, Stathmin 1 is highly expressed in leukemia cells and Stathmin 1 inhibition reduces the proliferation and clonogenicity. However, the clinical impact of Stathmin 1 expression, as well as, the consolidation of this protein as a potential therapeutic target in hematological malignancies remains poor explored. The aims of the present project are (i) to investigate the impact of Stathmin 1 expression in the clinical outcome of a well-characterized cohort of patients with acute promyelocytic leukemia, (ii) to investigate the effects of Stathmin 1 inhibition in leucemia cells in vitro and in vivo models, (iii) to identify and/or validate compounds capable of inhibiting Stathmin 1 and/or cause microtubules stability and to characterize them at cellular and molecular level. (AU)