Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Alessandro Beghini, PhD
Laboratory of Molecular Oncology
Dept. of Health Sciences
University of Milan
20142 Milan, Italy

- 1994 BSc in Biological Sciences, University of Milan, Italy
- 2000 PhD in Medical Genetics, University of Genova, Italy

- 1999-2001 Research Fellows, Medical Genetics, University of Milan, Italy
- 28/3-28/6/2014- Visiting Researcher presso il Department of Immunology, Genetics and Pathology, SciLifeLab, Biomedical Center, Uppsala University, Sweden (Prof. Ulf Landegren e Prof. Ola Söderberg).
- 15/04-15/05/2016- Visiting Researcher presso il Biomedical Center of Lund University, Lund, Sweden (Prof. Thomas Laurell).

- 2001-Present - Assistant Professor of Medical Genetics, University of Milan
- 2014 -National Scientific Qualification for Associate Professor in Molecular Biology

My research interest has been focused on cancer molecular genetics, and particularly on the receptor protein-tyrosine kinases driving oncogenic signal networks involved in the development of cancer. During the years (1995-2000) of PhD fellowship I obtained the first evidence for the involvement of KIT gene in the human AML, and particularly the peculiar association with core binding factor deranged-related neoplasms. In light of new recent findings, we envision that in a hematopoietic stem/progenitor cell context an elevated level of KIT receptor activity maintains cells in a proliferative, undifferentiated mode. Aberrant upregulation of endogenous KIT receptor activity in both CBF-AML and non-CBF-AML, regardless of the causing factor, would not only confer a proliferative advantage, but also contribute to keep myeloid cells in a differentiation-arrested stage. Moreover my research activity was addressing the KIT transduction signalling pathway, focusing on the negative regulation of KIT from which emerged the importance of the SHP1 (PTPN6) phosphatase. The diagnostic/prognostic value of KIT mutations has been recognized in the definition of molecular genetic alterations affecting clinical outcome of acute myeloid leukemia patients (WHO, 2008).The first hint that A-to-I RNA editing has fundamental implications in leukemic disorders derives from the detection of altered editing events in the protein tyrosine phosphatase 6 (PTPN6) transcripts in AML blasts.
In the first three years (2001-2003) as research fellow in Medical Genetics at the University of Milan I focused my interest on the puzzling rearrangements involving chromosome 19 in gliomagenesis following a single gene-based approach. A relevant step of my career advancement has been the independent characterization and cloning of a new gene, named MARK4, belonging to the microtubule affinity-regulating kinase (MARK) family.
In the last years, we showed an increase of WNT10B ligand expression and release within the microenvironment in the large majority in both leukemic blasts and stromal-like cells of AML patients, indicating its possible autocrine/paracrine involvement in the bone marrow microenvironment, and suggesting that the regenerative WNT signaling is a stem cell-associated function altered in AML AC133bright stem cell fraction. Specifically, WNT10B is expressed on both leukemic blasts and stromal-like cells, indicating a possible autocrine/paracrine involvement of Wnt in the bone marrow microenvironment, while activation of Wnt signaling marked by expression of the dephosphorylated beta-catenin is restricted to the AC133bright leukemic cells. This suggests the possibility that beta-catenin-activation requires the expression of specific FZD receptors, conferring a "responsive" phenotype restricted to a rare population of cells.
Recently we have obtained evidences for a recurrent rearrangement, which involved the WNT10B locus (WNT10BR) within intron 1 (IVS1) and flanked at the 5' by non-human sequences; it also expressed a transcript variant (WNT10BIVS1) which was mainly detected in a cohort of patients with intermediate/unfavorable risk AML.

1- Intronless WNT10B-short variant underlies new recurrent allele-specific rearrangement in acute myeloid leukemia
Lazzaroni F., Del Giacco L., Biasci D., Turrini M., Prosperi L., Brusamoilino R., Cairoli
R., Beghini A.
Scientific Reports: 6:37201, 2016. doi: 10.1038/srep37201
Corrigendum: Scientific Reports 2017 Apr 26;7:46788. doi: 10.1038/srep46788

2- miR-17 deregulates a core RUNX1-miRNA mechanism of CBF acute myeloid leukemia.
Fischer J., Rossetti S., Datta A., Eng K.H., Beghini A., Sacchi N.
Molecular Cancer 14(1): 7, 2015. doi: 10.1186/s12943-014-0283-z
Highlighted on Global Medical Discovery:

3- Successful treatment with imatinib in a patient with chronic eosinophilic leukemia, not otherwise categorized.
Iurlo A., Fracchiolla N.S., Ferla V., Cassin R., Gottardi E., Beghini A., Gianelli U., Spinelli O., Cortelezzi A.
J Clin Oncol: 32(10); e37-39, 2014

4- Regeneration-associated Wnt signaling is activated in long-term reconstituting AC133bright acute myeloid leukemia cells.
Beghini A, Corlazzoli F., Del Giacco L., Re M., Lazzaroni F., Brioschi M., Valentini G., Ferrazzi F., Ghilardi A., Righi M., Turrini M., Mignardi M., Cesana C., Bronte V., Nilsson M., Morra E., Cairoli R.
Neoplasia: 14(12): 1236-1248, 2012.

5- Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core binding factor subunits.
Brioschi M., Fischer J., Cairoli R., Rossetti S., Pezzetti L., Nichelatti M., Turrini M., Corlazzoli F., Scarpati B., Morra E., Sacchi N., Beghini A.
Neoplasia: 12(11): 866-876, 2010.

6- Prognostic impact of c-KIT mutations in Core Binding Factor Leukemias. An Italian retrospective study.
Cairoli R., Beghini A., Grillo G., Nadali G., Elice F., Ripamonti C.B., Colapietro P., Nichelatti M., Pezzetti L., Lunghi M., Cuneo A., Viola A., Ferrara F., Lazzarino M., Rodeghiero F., Pizzolo G., Larizza L., Morra E.
Blood: 107(9):3463-8, 2006.

7- The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines.
Beghini A., Magnani I., Roversi G., Piepoli T., DiTerlizzi S., Moroni R.F., Pollo B., Conti A.M.F., Cowell J.K., Finocchiaro G., Larizza L.
Oncogene 22:2581-2591, 2003.

8- RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia
Beghini A., Ripamonti C.B., Peterlongo P., Roversi G., Cairoli R., Morra E., Larizza L.
Human Molecular Genetics 9(15): 2297-2304, 2000.

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