PROJECT
SUPERVISORS
Project Supervisor
Valeria Santini
Background
I have a long standing interest in the biology of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and in the possibility to translate biological findings into clinically meaningful applications. As post graduate student, during my period in The Netherlands where I worked in the Cell Culture lab of Dr Daniel den Hoed Clinic/ Erasmus University Rotterdam under the supervision of Prof B. Loewenberg, I led a study that correlated in vitro non-stimulated proliferation of mononuclear leukemic cells to survival of AML patients. This publication was a first breakthrough linking biological and functional intrinsic characteristics of the leukemic cells to the clinical outcome (Lowenberg et al. N Engl J Med 1993).
At the time of the study this concept was not broadly accepted by the hematological community and its publication contributed to consolidate the reproducibility and sensitivity of in vitro leukemic cell culture and the relevance of in vitro growth evaluation for clinical applications.
Later in my carrier, I developed more interest in MDS, their biology and their treatment. Together with collaborators I contributed significantly to advancement in therapy of MDS being one of the first hematologist worldwide to treat patients with hypomethylating agents co-authoring a seminal work (Fenaux et al. Lancet Oncol 2009). Continuing in this direction, my group developed particular scientific curiosity defining the mechanism of action of azacitidine. I also analysed clinical effects of azacitidine and evaluation of response, as demonstrated by a long list of specific publications.
At present the work of my group has a central role in developing international strategies and clinical trials for improvement of outcome of MDS patients receiving hypomethylating agent (HMA) therapy.
Research
As group we are focused on the evaluation of the mechanisms of action of hypomethylating agents (HMAs, azacitidine and decitabine) in MDS therapy. For this reason, we focused our research on modulation of epigenetic mechanisms like DNA methylation, histone modifications and chromatin remodelling. In particular, we would like to dissect the different biological processes at the basis of primary resistance to azacitidine (and decitabine) versus secondary or adaptive resistance. In fact, the mechanisms at the basis of these two types of resistance are not understood and are most probably multifactorial.
We have shown that a peculiar pattern of DNA methylation predicts primary resistance in chronic myelomonocytic leukemia (CMML; a type of MDS/MPN disease), identifying 167 differentially methylated regions (DMRs) in responsive vs resistant cases (Meldi et al. JCI 2015). We also demonstrated that a main role in HMA resistance is represented by differential expression of specific enzymes involved in azanucleotides metabolism (Valencia A et al. Leukemia 2014).
In parallel, we are analysing by a specific high-throughput technique, the Enhanced Reduced Representation Bisulfite Sequencing (ERRBS), the genome-wide methylation profiles on a single nucleotide level. This technique combines restriction enzymes and bisulfite sequencing in order to enrich for the areas of the genome that have a high CpG content, and allows to evaluate different methylation regions (DMR), and to identify specific genomic regions differentially methylated at baeline and during HMA treatment. Preliminary data show substantial number of differentially methylated regions were identified in genomic areas outside of promoters, targeting enhancers and distal regulatory regions and gene expression signature seems to be different, suggesting the complexity of DNA methylation process inside MDS.
The aim of our group is to have a direct connection from bed to bench-side, answering to open scientific questions of direct relevance for MDS patient management.
Publications
Steensma DP et al. Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. J Clin Oncol. 2020
Bernard E et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020
Santini V. Enasidenib: a magic bullet for myelodysplastic syndromes? Lancet Haematol. 2020
Santini V. How I treat MDS after hypomethylating agent failure. Blood. 2019
Masala E et al. Severe hypoxia selects hematopoietic progenitors with stem cell potential from primary Myelodysplastic syndrome bone marrow cell culture. Oncotarget. 2018
Santini V. Of blood and bone: the sotatercept adventure. Lancet Haematol. 2018
Valencia-Martinez A et al. Mutated ASXL1 and number of somatic mutations as possible indicators of progression to chronic myelomonocytic leukemia of myelodysplastic syndromes with single or multilineage dysplasia. Haematologica. 2017
Meldi K et al. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest. 2015
Buchi F et al. Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target gene IL3. Epigenetics. 2014
Barbetti V et al. Time- and residue-specific differences in histone acetylation induced by VPA and SAHA in AML1/ETO-positive leukemia cells. Epigenetics. 2013