Brunangelo Falini Explained

Brunangelo Falini
Birth Date:5 August 1951
Birth Place:Perugia
Nationality:Italian
Occupation:Hematologist, academic and researcher
Awards:The Josè Carreras Award, European Hematology Association (EHA)
The “Leopold Griffuel” prize, French Association for Cancer Research (ARC)
The prize for “Excellence in Medicine”, American Italian Cancer Foundation (AICF)
The “Henry Stratton Medal”, American Society of Hematology (ASH)
Education:M.D.
Alma Mater:University of Perugia
Workplaces:University of Perugia

Brunangelo Falini is an Italian hematologist, academic and researcher. He is a Full Professor of Hematology, and Head of the Institute of Hematology and Bone Marrow Transplantation at University of Perugia.[1]

Falini serves as a member of the International Lymphoma Study Group (ILSG) and has been in the Clinical Advisory Committees for the WHO classification of lympho-hemopoietic tumors (2001, 2008 and 2017 versions). He has made discoveries in the field of acute myeloid leukemia (AML) and lymphomas, going from bench to bedside.[2]

Education

Falini received his M.D. degree in 1976, and completed his specialization in Internal Medicine at University of Perugia. He was Research Fellow at University of Southern California (1980-1981) working on the lymphoma classification and then in United Kingdom at John Radcliffe Hospital, Oxford (1982-1984) working on strategies for generating novel monoclonal antibodies against lymphoid-associated antigens.[1]

Research

Falini's research contributions fall in the area of precision medicine. His scientific activity ranges from the field of monoclonal antibodies for diagnostic and therapeutic purposes to genomic studies on AML and hairy cell leukemia (HCL). His discoveries of NPM1 mutations in AML and BRAF-V600E in HCL, identified new mechanisms of leukemogenesis and resulted into improvement of the diagnosis, prognostic stratification, molecular monitoring and therapy of these hematological malignancies.[2]

Monoclonal antibodies for diagnosis and therapy

Falini was a pioneer in the generation of novel monoclonal antibodies directed against oncoproteins involved in the pathogenesis of human lymphomas and leukemias,[3] such as PML, BCL6, MUM1-IRF4, nucleophosmin (NPM1), ALK and IRTA1. Falini also contributed to the development over time of modern classifications of lympho-hematopoietic neoplasms, including REAL (1994),[4] WHO (2001), WHO (2008), and WHO (2017), that he all co-signed. Using monoclonal antibodies against ALK and NPM1, Falini and colleagues took major steps forward in the biological and clinical characterization of ALK-positive anaplastic large-cell lymphoma (ALCL)[5] [6] and in the identification of NPM1-mutated AML, greatly contributing to their inclusion, as new disease entities, in the WHO classification of lympho-hemopoietic neoplasms.

Falini also led the team that generated and used for the first time an immunotoxin directed against the CD30 molecule[7] for the treatment of patients with refractory Hodgkin lymphoma.[8]

Cancer Genetics

In 2005, stemming from his immunohistological studies on ALK-positive ALCL, Falini discovered that tumor cells from about one-third of adult AML (mostly carrying a normal cytogenetic) expressed aberrantly in the cytoplasm nucleophosmin (a nucleolar located protein). This finding prompted Falini and colleagues to sequence the NPM1 gene and to discover heterozygous mutations at exon 12, responsible for the aberrant nuclear export of the NPM1 mutant protein.

Falini's group also demonstrated that NPM1 mutations are AML specific and associated with a de novo origin of the disease.[9] His research team then identified molecular variants of NPM1 mutations (other than exon 12), clarified the molecular mechanisms underlying the ectopic cytoplasmic accumulation of the NPM1 mutants[10] and proposed that it plays a critical role in leukemogenesis. Falini and colleagues also discovered a unique gene expression and microRNA profile of NPM1-mutated AML and demonstrated that over-expression of HOX genes is closely related to the cytoplasmic delocalization of NPM1 mutants.[11]

Falini's team also demonstrated for the first time that NPM1 and FLT3-ITD mutations frequently co-occur in AML patients and proposed their cooperative role in promoting leukemia.[9] Assessment of the NPM1 gene status and monitoring of measurable residual disease (MRD) by RT-quantitative PCR of NPM1 mutant copies (first reported by the Falini's group)[12] is now recommended by the LeukemiaNet for genetic stratification and guiding therapeutic decisions in AML patients.[13]

In 2011, using whole exome sequencing to further explore AML with normal karyotype, Falini led the team that first identified BCL6 co-repressor (BCOR) mutations as a new driver genetic lesion in AML and its association with DNMT3A mutations and with poor prognosis.[14]

In 2012, Falini and colleagues discovered that the BRAF-V600E mutation represents the causal genetic event in HCL, triggering transformation through the constitutive activation of the RAF-MEK-ERK signaling pathway.[15] Then, Falini's group went immediately from bench to bedside, establishing the first PCR diagnostic test for HCL[16] and demonstrating the high clinical benefit of the BRAF inhibitor vemurafenib in heavily pre-treated refractory/relapsed HCL patients.[17] More recently, Falini and colleagues reported that vemurafenib plus rituximab induces a durable complete response (often MRD negative) in most patients with refractory/relapsed HCL.[18]

In 2018, Falini's group analyzing the genome of thousands microdissected Hodgkin and Reed-Sternberg tumor cells discovered recurrent mutations of STAT3, STAT5B, JAK1, JAK2 and PTPN1 that support the pivotal role of aberrant activation of JAK-STAT signalling pathway in the molecular pathogenesis of Hodgkin lymphoma.[19]

Awards and honors

Bibliography

Notes and References

  1. Web site: Brunangelo Falini.
  2. Web site: Brunangelo Falini - Google Scholar.
  3. Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. 2002 . 10.1182/blood.V99.2.409 . Falini . Brunangelo . Mason . David Y. . Blood . 99 . 2 . 409–426 . 11781220 . 11515279 . free .
  4. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. 1994. 8068936. Harris. N. L.. Jaffe. E. S.. Stein. H.. Banks. P. M.. Chan. J. K.. Cleary. M. L.. Delsol. G.. De Wolf-Peeters. C.. Falini. B.. Gatter. K. C.. Blood. 84. 5. 1361–1392. 10.1182/blood.V84.5.1361.1361. free.
  5. ALK+ lymphoma: clinico-pathological findings and outcome. 1999 . 10194450. Falini . B. . Pileri . S. . Zinzani . P. L. . Carbone . A. . Zagonel . V. . Wolf-Peeters . C. . Verhoef . G. . Menestrina . F. . Todeschini . G. . Paulli . M. . Lazzarino . M. . Giardini . R. . Aiello . A. . Foss . H. D. . Araujo . I. . Fizzotti . M. . Pelicci . P. G. . Flenghi . L. . Martelli . M. F. . Santucci . A. . Blood . 93 . 8 . 2697–3306 .
  6. Lymphomas Expressing ALK Fusion Protein(s) Other Than NPM-ALK. Blood . 15 November 1999 . 94 . 10 . 3509–3515 . Falini . Brunangelo . Pulford . Karen . Pucciarini . Alessandra . Carbone . Antonino . De Wolf-Peeters . Chris . Cordell . Jacqueline . Fizzotti . Marco . Santucci . Antonella . Pelicci . Pier-Giuseppe . Pileri . Stefano . Campo . Elias . Ott . German . Delsol . Georges . Mason . David Y. . 10552961 .
  7. In vivo targeting of Hodgkin and Reed‐Sternberg cells of Hodgkin's disease with monoclonal antibody Ber‐H2 (CD30): immunohistological evidence. 1992. 10.1111/j.1365-2141.1992.tb04591.x. Falini. B.. Flenghi. L.. Fedeli. L.. Broe. M. K.. Bonino. C.. Stein. H.. Düurkop. H.. Bigerna. B.. Barbabietola. G.. Venturi. S.. Aversa. F.. Pizzolo. G.. Bartoli. A.. Pileri. S.. Sabattini. E.. And. R. Palumbo. Martelli. M. F.. British Journal of Haematology. 82. 1. 38–45. 1329918. 24225460.
  8. Response of refractory Hodgkin's disease to monoclonal anti-CD30 immunotoxin. 1992 . 10.1016/0140-6736(92)91135-U . Falini . B. . Flenghi . L. . Aversa . F. . Barbabietola . G. . Martelli . M.F . Comeli . P. . Tazzari . P.L . Broe . M.K . Stein . H. . Dürkop . H. . Pizzolo . G. . Bolognesi . A. . Stirpe . F. . Sabattini . E. . Pileri . S. . The Lancet . 339 . 8803 . 1195–1196 . 1349939 . 12943872 .
  9. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. 2005. 10.1056/nejmoa041974. Falini. Brunangelo. Mecucci. Cristina. Tiacci. Enrico. Alcalay. Myriam. Rosati. Roberto. Pasqualucci. Laura. La Starza. Roberta. Diverio. Daniela. Colombo. Emanuela. Santucci. Antonella. Bigerna. Barbara. Pacini. Roberta. Pucciarini. Alessandra. Liso. Arcangelo. Vignetti. Marco. Fazi. Paola. Meani. Natalia. Pettirossi. Valentina. Saglio. Giuseppe. Mandelli. Franco. Lo-Coco. Francesco. Pelicci. Pier-Giuseppe. Martelli. Massimo F.. GIMEMA Acute Leukemia Working Party. New England Journal of Medicine. 352. 3. 254–266. 15659725. free.
  10. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. 2006 . 10.1182/blood-2005-11-4745 . Falini . B. . Bolli . N. . Shan . J. . Martelli . M. P. . Liso . A. . Pucciarini . A. . Bigerna . B. . Pasqualucci . L. . Mannucci . R. . Rosati . R. . Gorello . P. . Diverio . D. . Roti . G. . Tiacci . E. . Cazzaniga . G. . Biondi . A. . Schnittger . S. . Haferlach . T. . Hiddemann . W. . Martelli . M. F. . Gu . W. . Mecucci . C. . Nicoletti . I. . Blood . 107 . 11 . 4514–4523 . 16455950 . 2434/602618 . 36362562 . free .
  11. Mutant NPM1 Maintains the Leukemic State through HOX Expression. 2018 . 10.1016/j.ccell.2018.08.005 . Brunetti . Lorenzo . Gundry . Michael C. . Sorcini . Daniele . Guzman . Anna G. . Huang . Yung-Hsin . Ramabadran . Raghav . Gionfriddo . Ilaria . Mezzasoma . Federica . Milano . Francesca . Nabet . Behnam . Buckley . Dennis L. . Kornblau . Steven M. . Lin . Charles Y. . Sportoletti . Paolo . Martelli . Maria Paola . Falini . Brunangelo . Goodell . Margaret A. . Cancer Cell . 34 . 3 . 499–512.e9 . 30205049 . 6159911 .
  12. Web site: Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations.
  13. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 2017. 5291965. Döhner. H.. Estey. E.. Grimwade. D.. Amadori. S.. Appelbaum. F. R.. Büchner. T.. Dombret. H.. Ebert. B. L.. Fenaux. P.. Larson. R. A.. Levine. R. L.. Lo-Coco. F.. Naoe. T.. Niederwieser. D.. Ossenkoppele. G. J.. Sanz. M.. Sierra. J.. Tallman. M. S.. Tien. H. F.. Wei. A. H.. Löwenberg. B.. Bloomfield. C. D.. Blood. 129. 4. 424–447. 10.1182/blood-2016-08-733196. 27895058.
  14. Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype. 2011 . 10.1182/blood-2011-07-365320 . Grossmann . Vera . Tiacci . Enrico . Holmes . Antony B. . Kohlmann . Alexander . Martelli . Maria Paola . Kern . Wolfgang . Spanhol-Rosseto . Ariele . Klein . Hans-Ulrich . Dugas . Martin . Schindela . Sonja . Trifonov . Vladimir . Schnittger . Susanne . Haferlach . Claudia . Bassan . Renato . Wells . Victoria A. . Spinelli . Orietta . Chan . Joseph . Rossi . Roberta . Baldoni . Stefano . De Carolis . Luca . Goetze . Katharina . Serve . Hubert . Peceny . Rudolf . Kreuzer . Karl-Anton . Oruzio . Daniel . Specchia . Giorgina . Di Raimondo . Francesco . Fabbiano . Francesco . Sborgia . Marco . Liso . Arcangelo . Blood . 118 . 23 . 6153–6163 . 22012066 . 1 . free .
  15. BRAF Mutations in Hairy-Cell Leukemia. 2011. 10.1056/NEJMoa1014209. Tiacci. Enrico. Trifonov. Vladimir. Schiavoni. Gianluca. Holmes. Antony. Kern. Wolfgang. Martelli. Maria Paola. Pucciarini. Alessandra. Bigerna. Barbara. Pacini. Roberta. Wells. Victoria A.. Sportoletti. Paolo. Pettirossi. Valentina. Mannucci. Roberta. Elliott. Oliver. Liso. Arcangelo. Ambrosetti. Achille. Pulsoni. Alessandro. Forconi. Francesco. Trentin. Livio. Semenzato. Gianpietro. Inghirami. Giorgio. Capponi. Monia. Di Raimondo. Francesco. Patti. Caterina. Arcaini. Luca. Musto. Pellegrino. Pileri. Stefano. Haferlach. Claudia. Schnittger. Susanne. Pizzolo. Giovanni. New England Journal of Medicine. 364. 24. 2305–2315. 21663470. 3689585. 1.
  16. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. 2012 . 10.1182/blood-2011-08-371179 . Tiacci . Enrico . Schiavoni . Gianluca . Forconi . Francesco . Santi . Alessia . Trentin . Livio . Ambrosetti . Achille . Cecchini . Debora . Sozzi . Elisa . Francia Di Celle . Paola . Di Bello . Cristiana . Pulsoni . Alessandro . Foà . Robin . Inghirami . Giorgio . Falini . Brunangelo . Blood . 119 . 1 . 192–195 . 22028477 . 14602781 . free . 2318/1823315 . free .
  17. Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. 2015. 10.1056/nejmoa1506583. Tiacci. Enrico. Park. Jae H.. De Carolis. Luca. Chung. Stephen S.. Broccoli. Alessandro. Scott. Sasinya. Zaja. Francesco. Devlin. Sean. Pulsoni. Alessandro. Chung. Young R.. Cimminiello. Michele. Kim. Eunhee. Rossi. Davide. Stone. Richard M.. Motta. Giovanna. Saven. Alan. Varettoni. Marzia. Altman. Jessica K.. Anastasia. Antonella. Grever. Michael R.. Ambrosetti. Achille. Rai. Kanti R.. Fraticelli. Vincenzo. Lacouture. Mario E.. Carella. Angelo M.. Levine. Ross L.. Leoni. Pietro. Rambaldi. Alessandro. Falzetti. Franca. Ascani. Stefano. New England Journal of Medicine. 373. 18. 1733–1747. 26352686. 4811324. 1.
  18. Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. 2021. 10.1056/NEJMoa2031298. Tiacci. Enrico. De Carolis. Luca. Simonetti. Edoardo. Capponi. Monia. Ambrosetti. Achille. Lucia. Eugenio. Antolino. Agostino. Pulsoni. Alessandro. Ferrari. Samantha. Zinzani. Pier L.. Ascani. Stefano. Perriello. Vincenzo M.. Rigacci. Luigi. Gaidano. Gianluca. Della Seta. Roberta. Frattarelli. Natalia. Falcucci. Paolo. Foà. Robin. Visani. Giuseppe. Zaja. Francesco. Falini. Brunangelo. New England Journal of Medicine. 384. 19. 1810–1823. 33979489. free.
  19. Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. 2018 . 10.1182/blood-2017-11-814913 . Tiacci . Enrico . Ladewig . Erik . Schiavoni . Gianluca . Penson . Alex . Fortini . Elisabetta . Pettirossi . Valentina . Wang . Yuchun . Rosseto . Ariele . Venanzi . Alessandra . Vlasevska . Sofija . Pacini . Roberta . Piattoni . Simonetta . Tabarrini . Alessia . Pucciarini . Alessandra . Bigerna . Barbara . Santi . Alessia . Gianni . Alessandro M. . Viviani . Simonetta . Cabras . Antonello . Ascani . Stefano . Crescenzi . Barbara . Mecucci . Cristina . Pasqualucci . Laura . Rabadan . Raul . Falini . Brunangelo . Blood . 131 . 22 . 2454–2465 . 29650799 . 6634958 .
  20. Web site: José Carreras Award.
  21. Web site: A Brunangelo Falini il prestigioso "Leopold Griffuel". YouTube.
  22. Web site: AICF's Prize for Scientific Excellence in Medicine.
  23. Web site: Henry M. Stratton Medal Recipients (Formerly Lecture) .

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