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Introduction
Skills and Expertise
Publications
Publications (200)
CRISPR-Cas gene editing has revolutionized experimental molecular biology over the past decade and holds great promise for the treatment of human genetic diseases. Here we review the development of CRISPR-Cas9/Cas12/Cas13 nucleases, DNA base editors, prime editors, and RNA base editors, focusing on the assessment and improvement of their editing pr...
Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressiv...
Background
Neuroblastoma is the most common extracranial solid tumor of childhood¹ and accounts for 12-15% of cancer-related deaths in children.² The survival of patients with refractory or relapsed neuroblastoma remains dismal.³ In neuroblastoma, chimeric antigen receptor (CAR) T cells against GD2 have shown encouraging clinical results, but relap...
Introduction
Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). Recently, molecularly targeted agents have shown promising activity against BM in NSCLC patients whose primary tumors carry ‘druggable’ mutations. However, it remains critical to identify specific pathogenic alte...
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-c...
For many cancer patients, chemotherapy produces untreatable life-long neurologic effects termed chemotherapy-related cognitive impairment (CRCI). We discovered that the chemotherapy methotrexate (MTX) adversely affects oxidative metabolism of non-cancerous choroid plexus (ChP) cells and the cerebrospinal fluid (CSF). We used a ChP-targeted adeno-as...
Key Points
The next-generation ALK inhibitors alectinib and lorlatinib are therapeutically active in ALK-positive large B-cell lymphoma (ALK-LBCL) We generated the first patient-derived xenograft model of ALK-LBCL and illustrate its potential to inform therapeutic options
CRISPR/Cas9-based genome editing has revolutionized experimental molecular biology and entered the clinical world for targeted gene therapy. Identifying DNA modifications occurring at CRISPR/Cas9 target sites is critical to determine efficiency and safety of editing tools. Here we show that insertions of LINE-1 (L1) retrotransposons can occur frequ...
Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). To identify targetable drivers of NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung sq...
Introduction
Mantle-cell lymphoma (MCL) is a B-cell non-Hodgkin Lymphoma (NHL) characterized by heterogenous behavior, ranging from indolent phenotype to highly aggressive and drug resistant one with dismal prognosis. Drug resistance may be generated by Tumor Microenvironment (TME), owing that Tumor-Associated Macrophages (TAM) are pathologically f...
Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN...
The expression of BCL6 in B cell lymphoma can be deregulated by chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in lymphoma or other tumors. Here, we show...
Neuroblastoma (NB) is the most deadly cancer in children with dismal survival in high-risk patients. The majority of NB express the full length anaplastic lymphoma kinase (ALK) receptor, that typically acts as driver oncogene together with MYCN. In contrast to ALK-driven lung cancer or lymphoma, targeted therapies with ALK tyrosine kinase inhibitor...
The ALK inhibitor crizotinib showed promising therapeutic efficacy for relapsed/refractory Anaplastic Large Cell Lymphoma (R/R ALCL). However, a fraction of ALK+ R/R ALCL patients do not achieve complete remission due to crizotinib resistance that develops within the first 3 months of therapy. In patients that achieve complete remission, crizotinib...
Significance
There are controversial data about the protumoral role of pancreatic cancer stroma, and dissecting multiple aspects will help to develop effective tailored therapies. Interleukin-17A (IL17A) has been reported to accelerate pancreatic acinar–ductal metaplasia, be important for maintaining stem-like cancer cells, and recruit immunosuppre...
Anaplastic large-cell lymphoma (ALCL) initially responds well to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) therapies (e.g., crizotinib); however, resistance appears once the treatment is concluded and persistent cells are not eradicated. ALCL preferentially grows around blood and lymphatic vessel in the lymph node, and our pr...
Introduction: Anaplastic large-cell lymphomas (ALCL) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. The ALK fusions activate several signaling pathways, promoting cell growth, migration, and survival. Chemotherapy is the standard treatment for ALCL patients, but about 30% of patients relapse. Targeting ALK u...
Simple Summary: Anaplastic lymphoma kinase positive anaplastic large cell lymphomas are a pediatric disease, which still needs treatment improvement. Crizotinib was the first ALK-targeted inhibitor used in clinics, but relapses are now known to occur. Current research efforts indicate that combined therapies could represent a superior strategy to e...
ALK positive Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin lymphoma characterized by expression of the NPM/ALK fusion tyrosine kinase essential for neoplastic cells growth. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. Although ALK+ ALCL cells are mainly driven by the constitutively ac...
Introduction: Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) family of cytidine deaminases provides a defense for the host genome against exogenous viruses and endogenous retro-elements, but their enzymatic activity may cause host genomic instability via a conversion of cytosine to uracil during RNA and DNA editing. While...
Introduction: EML4-ALK translocations are detected in 4-8 % of non-small cell lung cancer (NSCLC). While different EML4-ALK variants are defined by different breakpoints in the EML4 gene, most frequently located in intron 6 or 13, ALK breakpoint is almost invariably in intron 19. Rare reports describe EML4-ALK translocations with breakpoints in int...
Anaplastic Large Cell Lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive Anaplastic Lymphoma Kinase (ALK) fusion protein. ALK inhibitors such as crizotinib provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by NPM1-ALK fusion proteins achieved an objective r...
Objective
Immune checkpoint inhibitors (ICI) have become a major treatment in advanced non small cell lung cancer (NSCLC). However, some patients do not benefit from ICI, especially those harboring an ALK rearrangement. Here, we report a case of prolonged complete tumor response to immunotherapy in an ALK-rearranged NSCLC patient.
Materials and Met...
INTRODUCTION: Anaplastic large cell lymphomas (ALCL) frequently carry oncogenic fusion proteins as a consequence of chromosomal translocations of the anaplastic lymphoma kinase (ALK) gene. The fusion protein resulting from the translocation between dimerization domain of nucleophosmin (NPM) and intracellular tyrosine kinase domain of ALK activates...
CD40 has major roles in B cell development, activation, and germinal center responses. CD40 hypoactivity causes immunodeficiency whereas its overexpression causes autoimmunity and lymphomagenesis. To systematically identify B cell autonomous CD40 regulators, we use CRISPR/Cas9 genome-scale screens in Daudi B cells stimulated by multimeric CD40 liga...
CD40 has major roles in B cell development, activation, and germinal center responses. CD40 hypoactivity causes immunodeficiency whereas its overexpression causes autoimmunity and lymphomagenesis. To systematically identify B cell autonomous CD40 regulators, we use CRISPR/Cas9 genome-scale screens in Daudi B cells stimulated by multimeric CD40 liga...
RHO GTPases are a class of small molecules involved in the regulation of several cellular processes that belong to the RAS GTPase superfamily. The RHO family of GTPases includes several members that are further divided into two different groups: typical and atypical. Both typical and atypical RHO GTPases are critical transducers of intracellular si...
In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In...
Physiologically relevant ALK (anaplastic lymphoma kinase) expression was not detected in human and mouse monocytes and macrophages, suggesting that the effects of bioactive compounds on stimulator of interferon genes (STING) activation may not depend on ALK. Sepsis is a life-threatening condition associated with high lethality. The pathogenesis of...
Significance
Chromosomal rearrangements are early and essential events in the formation of many tumors. Two distinct end-joining pathways, classic and alternative nonhomologous end joining, can mediate rearrangement formation. Previous studies have shown that genetic factors mediating rearrangements differ significantly between mouse and human cell...
The CRISPR/Cas9 system has emerged as a powerful tool to edit the genome. Among many applications, the system generates the exciting possibility of engineering small and large portions of chromosomes to induce a variety of structural alterations such as deletions, inversions, insertions and inter-chromosomal translocations. Furthermore, the availab...
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC pa...
Chromosomal rearrangements, including translocations, are early and essential events in the formation of many tumors. Previous studies that defined the genetic requirements for rearrangement formation have identified differences between murine and human cells, most notably in the role of classical‐ and alternative-nonhomologous end joining factors...
The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and mu...
Introduction: BCL6 is a key oncogene in lymphoma pathogenesis. Malignant lymphoid cells exploit several mechanisms to deregulate the expression of BCL6, including chromosomal translocations, somatic mutations in the promoter regulatory regions, or inactivation of the pathway that controls its degradation. FBXO11 was recently identified as a major u...
Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clat...
The anaplastic lymphoma kinase (ALK) is recognized by the immune system as a tumor antigen, and preclinical evidence suggests that ALK-rearranged NSCLCs can also be successfully targeted immunologically using vaccine-based approaches. In contrast to ALK-rearranged lymphomas, the frequency and clinical significance of spontaneous ALK immune response...
Intra-tumor heterogeneity is a pervasive property of human cancers that poses a major clinical challenge. Here, we describe the characterization, at the transcriptional level, of the intra-tumor topography of two prominent breast cancer biomarkers and drug targets, epidermal growth factor receptor 2 (HER2) and estrogen receptor 1 (ER) in 49 archiva...
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the de...
Introduction: MYC and BCL2 overexpression assessed by IHC and rearrangement detected by FISH are important prognostic factor in Diffuse Large B-Cell Lymphoma (DLBCL). Double Hit Lymphoma (DHL) patients have a poor prognosis with conventional therapy and Double expressor Lymphoma (DE) have worse outcome compared with conventional DLBCL although data...
A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK-rearranged NSCLC are typically adenocarcinoma characterized by a solid signet-ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangeme...
List of primers used for genotyping, semi-quantitative reverse transcription PCR, real-time PCR primers and CNV analysis.
DOI:
http://dx.doi.org/10.7554/eLife.12116.020
Applications of the CRISPR-Cas9 system to edit the genome have widely expanded to include DNA gene knock-out, deletions, chromosomal rearrangements, RNA editing and genome-wide screenings. Here we show the application of CRISPR-Cas9 technology to edit the mouse and human immunoglobulin (Ig) genes. By delivering Cas9 and guide-RNA (gRNA) with retro-...
After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell...
Key Points
Rac1 and Cdc42 possess nonredundant roles in preventing apoptosis of NPM-ALK lymphoma cells. Simultaneous deletions of both Rac1 and Cdc42 prevents NPM-ALK lymphoma dissemination in vivo.
Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distr...
INTRODUCTION: We recently described inactivating mutations of the FBXO11 gene in Diffuse Large B Cell Lymphoma (DLBCL). One major function of FBXO11 is to regulate BCL6 stability as well as other targets such as SNAIL. BCL6 acts as an oncogene in several human B-cell lymphomas and its expression levels can be increased by several mechanisms includi...
Activation-induced cytidine deaminase (AID) is a B cell-specific enzyme that initiates class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes, essential mechanisms to generate different classes of antibody and antibody diversity for the antigens. At lower frequency, AID also promiscuously introduces DNA struct...
Introduction:
MYC and BCL2 overexpression and low BCL6 expression assessed by immunohistochemistry (IHC) have been reported as negative prognostic factors in DLBCL. We presented in a previous pilot study (Botto B, ASH 2014) a prognostic score based on overexpression of MYC, BCL2 and low expression of BLC6, assessed by IHC, in a retrospective cohort...
Non-Small Cell Lung Cancer (NSCLC) harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangements is successfully treated with ALK tyrosine kinase inhibitors (TKIs) for only a limited amount of time as most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response...
Noncoding RNAs have long been viewed as non-functional genomic relicts of evolution, but recetn findings have implicated their importance in physiology and disease. Recently, in vitro experiments demonstrated that the pseudogenes of PTEN and KRAS operate as natural miRNA decoys (competitive endogenous RNAs or ceRNAs) that regulate the expression of...
A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. More frequently ALK is juxtaposed to the echinoderm microtubule-associated protein-like 4 (EML4) gene on chromosome 2 and generates a constitutively active EML4-ALK fusion protein that triggers downstream oncogen...
Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein nucleophosmin (NPM)-ALK. NPM provides an oligomerization domain that causes the spontaneous dimerization and ligand-independent activation of the ALK. NPM-ALK deregulated kinase activity drives several pathways involved in cellular prolife...
Research over the past decade has suggested important roles for pseudogenes in physiology and disease. In vitro experiments demonstrated that pseudogenes contribute to cell transformation through several mechanisms. However, in vivo evidence for a causal role of pseudogenes in cancer development is lacking. Here, we report that mice engineered to o...
This study aims at developing an innovative theranostic approach for lung tumour and metastases treatment, based on Boron Neutron Capture Therapy (BNCT). It relies on to the use of Low Density Lipoproteins (LDL) as carriers able to maximize the selective uptake of boron atoms in tumor cells and, at the same time, to quantify the in vivo boron distr...
Non-coding RNAs have long been viewed as non-functional genomic relicts of evolution, but recetn findings have implicated their importance in physiology and disease. Recently, in vitro experiments demonstrated that the pseudogenes of PTEN and KRAS operate as natural miRNA decoys (competitive endogenous RNAs or ceRNAs) that regulate the expression o...
Generation of genetically engineered mouse models (GEMMs) for chromosomal translocations in the endogenous loci by a knockin strategy is lengthy and costly. The CRISPR/Cas9 system provides an innovative and flexible approach for genome engineering of genomic loci in vitro and in vivo. Here, we report the use of the CRISPR/Cas9 system for engineerin...
Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in th...
