The goal of the group is to identify at the genomic and transcriptomic level the networks of acquired and inherited aberrations that drive the development and the progression of B ALL and JMML. Indeed, the group has a strong expertise in generation, analysis and integration of data supporting the improvement of diagnosis, risk stratification and treatment of leukemia pediatric patients supported by experimental and functional studies.
The main projects of the group are:
i) biology of somatogenetic architecture and clonal evolution of Juvenile Myelomonocytic Leukemia (JMML), a rare pediatric hematological disease characterized by excessive proliferation of monocytes and granulocytic cells, an aggressive disease course and a high risk of treatment failure. – the 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 and transcriptomic alterations in the hematopoietic cell hierarchy to reconstruct the clonal phylogeny and its correlation within clinically distinct groups of JMML patients; the study also focuses on the development of an in vitro and in vivo model able to recapitulate key pathophysiology features of JMML disease and to trace the clone’s dynamicity.
ii) circular RNA (circRNA) in normal hematopoiesis and in high risk B-ALL: circRNAs are an emerging class of stable transcriptome members that participate in circuits competing for binding of miRNAs, RNA-binding proteins (RBPs) or translation initiation and are part of key oncogenic axes; the project aims at the identification and validation of specific circRNAs dysregulated in high risk B ALL as compared to normal hematopoiesis, predict circRNA functions and interactions by computational analysis and experimental studies, and to better understand their origin and role in the disease to be further integrated with known disease associated molecular networks; this work is part of a collaborative effort with Prof. Stefania Bortoluzzi.
iii) precision medicine and clonal evolution investigation of high risk B-ALL: In the last decade a great advance in the comprehension of the genetic and biological bases of child-hood leukemia has been achieved and genomic analysis contributed to the improvement of risk stratification and patient treatment, however about 20% of BALL patients present treatment resistance and relapse; our group is involved in the identification of genomic and transcriptomic alterations of high risk BALL patients and in particular of therapy resistant and relapsed patients;we characterize by different omics approaches (exome, RNA-seq, gene expression profiling) driver mutations in BALL patients to identify drug resistance mechanisms and clonal structure and track clonal dynamicity between diagnosis and relapse.
iv) predisposition to inherited leukemia: 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 somatogenetic 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 for ALL development; these evidences provide the rationale 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. 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. Ongoing studies are exanimating genetic basis by NGS that predispose to leukemia and also other hematological malignancies.
v) role of exosomes in treatment response kinetics and microenvironment modulation in BALL leukemia: the group is using different approaches to identify novel markers to improve diagnosis, prognosis and patients’ follow-up able to facilitate the introduction of tailored treatment regimens in selected groups of patients; in this area, circulating exosomes represent a promising source of biomarkers and many evidences suggest their influence in the crosstalk with tumor and microenvironment cells. We are now studying by RNA-seq the small RNA cargo from isolated from plasmatic exosomes at diagnosis and during follow-up in a cohort of BALL and lymphoma patients as part of a collaborative study. Furthermore, we will investigate exosome-mediated sRNAs transfer from the tumor microenvironment and leukemia cells and vice versa using and in vitro model.
Alice Cani, Post-Doctoral Fellow
Caterina Tretti, PhD Students
Marzollo A, Maestrini G, La Starza R, Elia L, Malfona F, Pierini T, Tretti Parenzan C, Coppe A, Bortoluzzi S, Biffi A, Mecucci C, Bresolin S*, Testi AM* A novel germline variant in PIK3R1 results in SHORT syndrome associated with TAL/LMO T-cell Acute Lymphoblastic Leukemia. Am J Hematol. 2020 Sep 16;
Zhou Y, Han C, Wang E, Lorch AH, Serafin V, Cho BK, Gutierrez Diaz BT, Calvo J, Fang C, Khodadadi-Jamayran A, Tabaglio T, Marier C, Kuchmiy A, Sun L, Yacu G, Filip SK, Jin Q, Takahashi YH, Amici DR, Rendleman EJ, Rawat R, Bresolin S, Paganin M, Zhang C, Li H, Kandela I, Politanska Y, Abdala-Valencia H, Mendillo ML, Zhu P, Palhais B,
Van Vlierberghe P, Taghon T, Aifantis I, Goo YA, Guccione E, Heguy A, Tsirigos A, Wee KB, Mishra RK, Pflumio F, Accordi B, Basso G, Ntziachristos P. Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia. Cancer Discov. 2020 Sep;10(9):1388-1409;
Dal Molin A, Bresolin S, Gaffo E, Tretti C, Boldrin E, Meyer LH, Guglielmelli P, Vannucchi AM, TeKronnie G, Bortoluzzi S. CircRNAs Are Here to Stay: A Perspective on the MLL Recombinome Front Genet. 2019 Feb 13;10:88;
Coppe A, Nogara L, Pizzuto MS, Cani A, Cesaro S, Masetti R, Locatelli F, TeKronnie G, Basso G, Bortoluzzi S, Bresolin S. Somatic mutations activating Wiskott-Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients. Hum Mutat. 2018 Apr;39(4):579-587;
Binatti A, Bresolin S, Bortoluzzi S, Coppe A. iWhale: a computational pipeline based on Docker and SCons for detection and annotation of somatic variants in cancer WES data. Brief Bioinform. 2020 May 20:bbaa065;
Helsmoortel HH*, Bresolin S*, Lammens T, Cavé H, Noellke P, Caye A, Ghazavi F, de Vries A, Hasle H, Labarque V, Masetti R, Stary J, van den Heuvel-Eibrink MM, Philippé J, Van Roy N, Benoit Y, Speleman F, Niemeyer C, Flotho C, Basso G, TeKronnie G, Van Vlierberghe P, De Moerloose B. LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia. Blood. 2016 Mar 3;127(9):1163-7;
Bresolin S, De Filippi P, Vendemini F, D’Alia M, Zecca M, Meyer LH, Danesino C, Locatelli F, Masetti R, Basso G, Te Kronnie G. Mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia: a report from the Italian AIEOP study group. Oncotarget. 2016 May 17;7(20):28914-9;
Azzolin L*, Zanconato F*, Bresolin S, Forcato M, Basso G, Bicciato S, Cordenonsi M, Piccolo S. Role of TAZ as mediator of Wntsignaling.Cell. 2012 Dec 21;151(7):1443-56;
Kohlmann A, Klein HU, Weissmann S, Bresolin S, Chaplin T, Cuppens H, Haschke-Becher E, Garicochea B, Grossmann V, Hanczaruk B, Hebestreit K, Gabriel C, Iacobucci I, Jansen JH, te Kronnie G, van de Locht L, Martinelli G, McGowan K, Schweiger MR, Timmermann B, Vandenberghe P, Young BD, Dugas M, Haferlach T. Leukemia. The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories. 2011 Dec;25(12):1840-8;
Bresolin S, Zecca M, Flotho C, Trentin L, Zangrando A, Sainati L, Stary J, de Moerloose B, Hasle H, Niemeyer CM, TeKronnie G, Locatelli F, Basso G. Gene expression-based classification as an independent predictor of clinical outcome in juvenile myelomonocytic leukemia. J Clin Oncol. 2010 Apr 10;28(11):1919-27;