- Leukemia studies in animal models. We studied canine leukemia and lymphoma contributing to elucidate the role of genetic modifications involved in the pathogenesis of these diseases in dogs and human patients.
- Development of an acute lymphoblastic leukemia model with CNS infiltration in zebrafish. In order to understand the molecular mechanisms of lymphoblast CNS infiltration in acute lymphoblastic leukemia and lymphoma we studied the molecular mechanism of CNS infiltration in two zebrafish models.
- Screening of point mutations of IKZF1 gene by next generation amplicon deep sequencing of Philadelphia positive (Ph+) acute lymphoblastic leukemia. In this collaborative study that involved five leukemia research centers across Europe we analyzed 98 patients with no indications of IKZF1 Twelve patients were found to carry a deleterious point mutation in IKZF1. This refinement of IKZF1 mutational status increased the percentage of Ph+ patients with aberrant IKZF1, which is associated to an inferior clinical response.
- Microvesicles (MVs) as carriers of oncogenic messages. We analyzed RNA transcript cargo of MVs shed from K562 CML cells identifying oncogenic BCR-ABL1 pathway transcripts and messengers related to basal cellular functions. Co-culture of K562 derived MVs with healthy mesenchymal cells showed transfer of the oncogenic message and confirmed MV-dosage dependent increase of mesenchymal cell proliferation.
- Biology of Somatogenetic Architecture And Clonal Evolution of Juvenile Myelomonocytic Leukemia. This project investigates the somatogenetic architecture of JMML to understand the grade of tumor heterogeneity in the bone marrow of patients and the sequential acquisition of mutations in the hematopoietic cell hierarchy to reconstruct the clonal phylogeny and its correlation with clinically distinct groups of JMML patients.
- Circular RNA (circRNA) in normal hematopoiesis. Recent studies made clear that circular RNAs (circRNAs) are particularly stable transcriptome members with distinctive features. CircRNA biogenesis and functions that we recently reviewed showed circRNAs modulate host gene expression, but also participate in circuits competing for binding of miRNAs, RNA-binding proteins (RBPs) or translation initiation, and are part of key oncogenic axes. RNA-seq identified thousands of circRNAs with developmental stage- and tissue-specific expression and our first results of a collaborative project with Prof. Stefania Bortoluzzi showed that circRNAs are abundantly expressed in the hematopoietic compartment. Analysis of specific circRNA expression in hematopoietic cellular subtypes, validation of RNAseq data and prediction of functional features e.g. interactions with miRNAs, proteins and other regulatory elements are un-going.
- Mutational Screening of high risk resistant B-ALL. Although the treatment of pediatric leukemia is considered one of the best achievements in medicine, about 20% of B-ALL patients present treatment resistance and relapse. In this project we perform whole exome sequencing and gene expression profiling of samples of B-ALL patient with resistance to therapy or leukemia relapse. Identified new genomic and transcriptome aberration will guide leukemia research to direct patients care in the hematology-oncology ward.
- Predisposition to Inherited ALL. Clinicians have known since decades that families with ALL in subsequent generations may point to hereditary genetic components, even if ALL in the vast majority of the cases is considered an acquired disease of somato-genetic origin. Some point mutations in PAX5, ETV6 and IKZF1 were recently reported to be present in families with recurrent ALL and confer an increased risk to ALL development. These studies provide the rational to identify disease related mutations in families with recurrent ALL. Inherited or de novo acquired constitutional mutations in genes are likely to impact the phenotype of the leukemia altering the biology of the aberrant cells, the systemic response to current therapies and the long term disease free survival of patients. Thus therapies may require adjustments and/or provide opportunities to develop specific therapies for these cases. Being inherited ALL a rare variant of a common disorder the only way to meaningfully address these issues is through direct collaborations. Since November 2017 we joined a European program (COST-Action –CA16223) that joins 24 countries across Europe in a joint effort to improve the understanding of leukemia predisposition in pediatric patients, to improve patient care, and enable genetic counseling of patients and families.
- Silvia Bresolin
- Alice Cani
- Elena Boldrin
Selected PubblicationsStanulla M, Dagdan E, Zaliova M, Möricke A, Palmi C, Cazzaniga G, Eckert C, Te Kronnie G, Bourquin JP, Bornhauser B, Koehler R, Bartram CR, Ludwig WD, Bleckmann K, Groeneveld-Krentz S, Schewe D, Junk SV, Hinze L, Klein N, Kratz CP, Biondi A, Borkhardt A, Kulozik A, Muckenthaler MU, Basso G, Valsecchi MG, Izraeli S, Petersen BS, Franke A, Dörge P, Steinemann D, Haas OA, Panzer-Grümayer R, Cavé H, Houlston RS, Cario G, Schrappe M, Zimmermann M. 2018. TRANSCALL Consortium; International BFM Study Group. IKZF1plus Defines a New Minimal Residual Disease-Dependent Very-Poor Prognostic Profile in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia. J Clin Oncol, JCO2017743617. doi: 10.1200/JCO.2017.74.3617
Coppe A, Nogara L, Pizzuto MS, Cani A, Cesaro S, Masetti R, Locatelli F, Te Kronnie G*, Basso G, Bortoluzzi S, Bresolin S.. 2018. Somatic mutations activating Wiskott-Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients. Hum Mutat, doi: 10.1002/humu.23399
Milani G, Lana T, Bresolin S, Aveic S, Pastò A, Frasson C, Te Kronnie G*. 2017. Expression Profiling of Circulating Microvesicles Reveals Intercellular Transmission of Oncogenic Pathways. Mol Cancer Res, 683-695. doi: 10.1158/1541-7786.MCR-16-0307
Lana T, de Lorenzo P, Bresolin S, Bronzini I, den Boer ML, Cavé H, Froňková E, Stanulla M, Zaliova M, Harrison CJ, de Groot H, Valsecchi MG, Biondi A, Basso G, Cazzaniga G, te Kronnie G.. 2015. Refinement of IKZF1 status in pediatric Philadelphia-positive acute lymphoblastic leukemia. Leukemia, doi: 10.1038/leu.2015.78
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