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]

NPM1 immunostaining

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]