Cell death, differentiation and cancer

Team project

Team #2 is interested in analysing the role of caspases and autophagy in the differentiation and pathophysiology of haematopoietic cells. Concurrently, we also scrutinized the mechanisms of resistance to tyrosine kinase inhibitors, nucleoside analogues and proteasome inhibitors, the leading treatments for chronic myelogenous leukaemia (CML), myelodysplastic syndromes (MDS) and multiple myeloma (MM).

Previous activities

Bcl-2 family members play an essential role in the control of apoptosis and autophagy and alterations of these processes are intimately linked with haematopoietic cell transformation. In this context, we identified an anti-apoptotic member of the Bcl2 family, Bcl-B as a new biomarker for MM, that also predicts the resistance to Vidaza® (5-azacytidine, a nucleoside analogue) at diagnosis in MDS patients. An original triazole nucleoside analogue developed in collaboration with the Chemistry Institute of Nice (CNRS7272) has now been licenced and this drug will likely enter phase I clinical trial in high-risk MDS patients. Finally, we generated transgenic mice in which the expression of the Bcl-B transgene is driven by the Eu-promoter specifically in the B cell compartment. These mice developed with age a haematopoietic malignancy that accurately replicates human MM, highlighting the key role of Bcl-B as an essential survival factor in plasmocyte differentiation and transformation.

Research Projects

Our research programme will focus on the pathophysiology and the treatment of several myeloid malignancies including MDS, acute myeloid leukaemia (AML), chronic myelomonocytic leukaemia (CMML) as well as MM. We will perform fundamental, preclinical and translational researches, studying also normal haematopoiesis for a better understanding of haematopoietic malignancy mechanisms. One of our main goals is to decipher the role of Bcl-B in myeloid malignancies and MM. We also discovered that autophagy plays a key role in the physiological differentiation of monocytes into macrophages. We showed that modulating autophagy and differentiation could represent a new therapeutic avenue in patients suffering from CMML. We identified in CMML patients a subpopulation of myeloid-derived suppressive cells (MDSCs) able to alter monocyte differentiation. In MDS, we established that Bcl-B is a new biomarker of resistance to Vidaza®. We are currently studying the role of bone marrow stromal cells in the resistance to Vidaza® and the effect of a promising family of nucleoside analogues for MDS treatment. In addition, we identified that MDS resistant cells and some AML cell lines exhibited a defect in chaperone-mediated autophagy that can be therapeutically exploited. Finally, we demonstrated that Bcl-B plays an essential role in the differentiation of plasmocytes by protecting them from cell death. In this context, our project will be developed along 3 research axis.

Axis#1: Deciphering the mechanisms of resistance to Aza in MDS/AML.

Axis#2: Dissecting the mechanisms involved in macrophage differentiation of monocytes and their alterations in CMML.

Axis#3: Investigating the role of Bcl-B in the pathophysiology of MM.

These 3 highly complementary projects will bring new and key information regarding the pathophysiology and treatment of several currently incurable haematopoietic malignancies.

Highlights

Over the 2010-2016 period, members of the Team 2 have contributed to significant advances in the field of oncohematology and resistance of hematopoietic malignancies to chemotherapies. We :

1) Developped an original transgenic mouse model which replicates accurately human MM. This mouse model represents an unvaluable tool for evaluating anti-myeloma therapies (Autophagy, 2012a, J Exp Med, 2016, Patent 2015).

2) Deciphered the signalling pathways involved in the differentiation of monocytes into macrophages, established the key role of AMPK and autophagy in this process and proposed new therapies targeting AMPK and autophagy in CMML (Autophagy 2009, Blood 2012, Autophagy, 2012b and 2015, Patent with Inserm Transfer 2015).

3) Identified the anti-apoptotic Bcl2 family member Bcl-B as a new marker of resistance to Azacytidine in MDS (Oncotarget 2012, 2014, WO-Patent 2012, Matwin 2013), validated new nucleoside analogues for the treatment of this disease (Oncotarget 2012, 2014) and licenced 2 patents to Clevexel Pharma for the diagnosis of Aza resistance in MDS/AML patients.

4) Identified defect in chaperone-mediated autophagy (due to LAMP2 deficiency) in MDS and AML (manuscript in preparation, Patent with Inserm transfert 2016).

5) Conducted a phase I/II clinical trial analyzing the impact of Acadra (Acadesine) in Aza-resistant MDS and AML patients.

6) Finally, Team 2 developped fruitful collaborations with Teams 1, 3, 4, 5, 6, 7, 11, 12 at C3M (Haematologica, 2012, Cancer Res 2010 and 2011, Plos Pathogen 2015, PNAS 2013, Leukemia 2013 and 2015).

Team Publications

Team Leader

Patrick Auberger