Tackling primary induction failure in childhood acute myeloid leukaemia by a deeper knowledge of molecular haematopoiesis: novel markers and therapeutic targets

Acute myeloid leukemia (AML) is an aggressive heterogenous malignancy that involves immature myeloid progenitor cells that produce red blood cells, platelets and granulocytes. It occurs when myeloid stem cells become cancerous leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). They can proliferate rapidly. Standard conventional therapy is not always resolutive because 5-40% of AML patients including paediatric and adult, do not achieve remission and are defined are Primary Induction Failure (PIF). Currently, the molecular basis for the lack of response to conventional induction therapies in childhood AML is still unclear and it is imperative to unveil as soon as possible the molecular background to determine the absence of chemo-therapy response. For this reason, a better knowledge of pathogenetic and molecular features of AML will permit a more accurate stratification driving appropriate induction and post-induction therapies. The present project aims to confirm the overexpression of selected genes identified in our laboratories analysing four different international cohorts in enlarge AML patients by Elisa assays and quantitative real-time. In parallel, the biochemical and functional characterization of one of these, the serine protease inhibitor Kazal-type 2, will give crucial clues to module its expression by silencing or therapeutic inhibitors to restore physiological interaction between hematopoietic stem/progenitor and surrounding cells. 2D and 3D cell models will be set up to better explore and achieve these objectives. It is known that Formyl Peptide Receptors (FPRs) are involved in the activation of granulopoiesis. Therefore, analysis of the effects of FPRs stimulation can contribute to clarify the role of serine proteases in the intercellular communication and identify new potential therapeutic target involved in hematopoietic homeostasis.

• cancer biochemistry
• predictive bio-markers
• chemo-resistance
• serine proteases
• signal transduction
• 2D and 3D cell models