Title: Understanding mechanisms of NFIC in regulating AML development and progression
Funder: Health and Care Research Wales (Welsh Government)

Abstract: Acute myeloid leukaemia (AML) is an aggressive form of blood cancer which has different subtypes making it a difficult disease to treat. Current chemotherapeutic treatments are unpleasant, highly toxic, often fail and long-term survival of patients is poor. The only prospect for improved outcomes for most patients is the development of targeted treatments. Therefore, there is a clear need to identify and validate new therapeutic targets for AML therapy. A unifying feature of AML is that normal blood cell development is blocked. It is not surprising therefore that the processes that regulate development are frequently disrupted in this disease. To determine the proteins that may lead to a block in blood cell development and altered cancer cell growth, we analysed AML patient cancer cells (blasts) by Mass Spectrometry. This is a technology which allowed us to identify proteins that have been changed in blood cancer cells from AML patients compared to blood cells from normal individuals. One such protein is known as Nuclear Factor I-C (NFIC). We found that increasing the level of this protein disturbs the process of normal blood cell formation which is one of the major reasons for AML development. Importantly, when we decreased NFIC protein in AML cells, these cells stopped growing, ultimately killing them. We now want to establish the mechanism to determine how NFIC contributes to AML growth and development by identifying the other proteins that mediates NFIC function in these cells. This study will not only allow us to better understand AML but will also identify NFIC or its associated proteins as valuable molecules for development of new and less toxic therapies for the treatment of AML.

Lay abstract: Acute myeloid leukaemia (AML) is an aggressive form of blood cancer which has different subtypes making it a difficult disease to treat. Current chemotherapeutic treatments are unpleasant, highly toxic, often fail and long-term survival of patients is poor. The only prospect for improved outcomes for most patients is the development of targeted treatments. Therefore, there is a clear need to identify and validate new therapeutic targets for AML therapy. A unifying feature of AML is that normal blood cell development is blocked. It is not surprising therefore that the processes that regulate development are frequently disrupted in this disease. To determine the proteins that may lead to a block in blood cell development and altered cancer cell growth, we analysed AML patient cancer cells (blasts) by Mass Spectrometry. This is a technology which allowed us to identify proteins that have been changed in blood cancer cells from AML patients compared to blood cells from normal individuals. One such protein is known as Nuclear Factor I-C (NFIC). We found that increasing the level of this protein disturbs the process of normal blood cell formation which is one of the major reasons for AML development. Importantly, when we decreased NFIC protein in AML cells, these cells stopped growing, ultimately killing them. We now want to establish the mechanism to determine how NFIC contributes to AML growth and development by identifying the other proteins that mediates NFIC function in these cells. This study will not only allow us to better understand AML but will also identify NFIC or its associated proteins as valuable molecules for development of new and less toxic therapies for the treatment of AML.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS