Brunangelo Falini | |
---|---|
Born | Perugia | August 5, 1951
Nationality | Italian |
Occupation(s) | 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) |
Academic background | |
Education | M.D. |
Alma mater | University of Perugia |
Academic work | |
Institutions | 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]
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]
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]
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]
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]
Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising,bone pain,fatigue,fever,and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on,there are typically no symptoms. Later,non-painful lymph node swelling,feeling tired,fever,night sweats,or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.
Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood,bone marrow,lymph,and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system,a disease affecting one will often affect the others as well,making aplasia,myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors,chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"),and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous");these other blood conditions may also be managed by a hematologist.
Anaplastic large-cell lymphoma (ALCL) refers to a group of non-Hodgkin lymphomas in which aberrant T cells proliferate uncontrollably. Considered as a single entity,ALCL is the most common type of peripheral lymphoma and represents ~10% of all peripheral lymphomas in children. The incidence of ALCL is estimated to be 0.25 cases per 100,000 people in the United States of America. There are four distinct types of anaplastic large-cell lymphomas that on microscopic examination share certain key histopathological features and tumor marker proteins. However,the four types have very different clinical presentations,gene abnormalities,prognoses,and/or treatments.
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all leukemias,with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells,characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired,shortness of breath,easy bruising and bleeding,and increased risk of infection. Occasionally,spread may occur to the brain,skin,or gums. As an acute leukemia,AML progresses rapidly,and is typically fatal within weeks or months if left untreated.
Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells,a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults,with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals,with a median age of diagnosis at ~70 years,although it can occur in young adults and,in rare cases,children. DLBCL can arise in virtually any part of the body and,depending on various factors,is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms,e.g. fever,weight loss,and night sweats.
Chronic myelomonocytic leukemia (CMML) is a type of leukemia,which are cancers of the blood-forming cells of the bone marrow. In adults,blood cells are formed in the bone marrow,by a process that is known as haematopoiesis. In CMML,there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow,as well as abnormal looking cells (dysplasia) in at least one type of blood cell.
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3,receptor-type tyrosine-protein kinase FLT3,or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the FLT3 gene. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase class III. CD135 is the receptor for the cytokine Flt3 ligand (FLT3L).
BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B,while the protein is more formally known as serine/threonine-protein kinase B-Raf.
Nucleophosmin (NPM),also known as nucleolar phosphoprotein B23 or numatrin,is a protein that in humans is encoded by the NPM1 gene.
Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic condition in which individuals have increased blood levels of particular subtypes of monoclonal lymphocytes. This increase must persist for at least 3 months. The lymphocyte subtypes are B-cells that share certain features with the abnormal clones of lymphocytes that circulate in chronic lymphocytic leukemia/small lymphocyte lymphoma (CLL/SLL) or,less frequently,other types of B-cell malignancies. Some individuals with these circulating B-cells develop CLL/SLL or the lymphoma types indicated by their circulating monoclonal B-cells. Hence,MBL is a premalignant disorder
Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity,it cannot be used as a drug itself;instead,it is linked to a monoclonal antibody (MAB) which directs it to the cancer cells. In International Nonproprietary Names for MMAE-MAB-conjugates,the name vedotin refers to MMAE plus its linking structure to the antibody. It is a potent antimitotic drug derived from peptides occurring in marine shell-less mollusc Dolabella auricularia called dolastatins which show potent activity in preclinical studies,both in vitro and in vivo,against a range of lymphomas,leukemia and solid tumors. These drugs show potency of up to 200 times that of vinblastine,another antimitotic drug used for Hodgkin lymphoma as well as other types of cancer.
Vemurafenib (INN),sold under the brand name Zelboraf,is a medication used for the treatment of late-stage melanoma. It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.
V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses,including melanoma,hairy cell leukemia,papillary thyroid carcinoma,colorectal cancer,non-small-cell lung cancer,Langerhans cell histiocytosis,Erdheim–Chester disease and ameloblastoma.
David G. Maloney is an oncologist and researcher at Fred Hutchinson Cancer Research Center and the University of Washington who specializes in developing targeted immunotherapies for the treatment of blood cancers.
Camidanlumab tesirine is an antibody-drug conjugate (ADC) composed of a human antibody that binds to the protein CD25,conjugated to a pyrrolobenzodiazepine dimer toxin. The experimental drug,developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL),and for the treatment of B-cell acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Mature T-cell lymphoma,also called peripheral T-cell lymphoma,is a group of rare,aggressive lymphomas that develop from mature white blood cells and originate from lymphoid tissues outside of the bone marrow. Mature T-cell lymphoma is under the category of non-Hodgkin lymphoma. Mature T-cell lymphomas account for 10% to 15% of all lymphomas and is more common in Asia than in Europe and America. Its common subtypes include angioimmunoblastic T-cell lymphoma,anaplastic large cell lymphoma and peripheral T-cell lymphoma not otherwise specified. While different subtypes have variable symptoms,common symptoms include enlarged painless lymph nodes,fever,weight loss,rash and night sweats.