Franck Rapaport

Franck Rapaport
Sanofi | SHANTHA · Data and data science

PhD

About

97
Publications
10,775
Reads
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4,622
Citations
Additional affiliations
August 2017 - present
The Rockefeller University
Position
  • Instructor
July 2014 - August 2017
Memorial Sloan Kettering Cancer Center
Position
  • Computational research leader
July 2011 - July 2014
Memorial Sloan Kettering Cancer Center
Position
  • Senior Researcher

Publications

Publications (97)
Article
Full-text available
A large number of computational methods have been developed for analyzing differential gene expression in RNA-seq data. We describe a comprehensive evaluation of common methods using the SEQC benchmark dataset and ENCODE data. We consider a number of key features, including normalization, accuracy of differential expression detection and differenti...
Article
Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores an...
Article
Full-text available
Microarrays have become extremely useful for analysing genetic phenomena, but establishing a relation between microarray analysis results (typically a list of genes) and their biological significance is often difficult. Currently, the standard approach is to map a posteriori the results onto gene networks in order to elucidate the functions perturb...
Article
Full-text available
Cancer progression is often driven by an accumulation of genetic changes but also accompanied by increasing genomic instability. These processes lead to a complicated landscape of copy number alterations (CNAs) within individual tumors and great diversity across tumor samples. High resolution array-based comparative genomic hybridization (aCGH) is...
Article
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients present episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is p...
Article
Full-text available
Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that th...
Article
Full-text available
The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient’s leukocytes did not express PD-1 or respond to PD-1-mediated suppress...
Article
We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, includin...
Article
We study a patient with the human papilloma virus (HPV)-2-driven “tree-man” phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. The...
Article
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 v...
Article
Purpose: Biomarkers of response and resistance to FLT3 tyrosine kinase inhibitors (TKI) are still emerging, and optimal clinical combinations remain unclear. The purpose of this study is to identify co-occurring mutations that influence clinical response to the novel FLT3 inhibitor pexidartinib (PLX3397). Experimental design: We performed target...
Article
Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette–Guérin-osis and disseminated tubercul...
Article
Full-text available
PurposeGermline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.Methods We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe...
Article
Full-text available
Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumon...
Article
Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five m...
Article
Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by BCG vaccines and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity, due to mutations of 15 genes controlling the production of, or response to IFN-γ. Since the first...
Preprint
Full-text available
Background Genetic variants underlying severe diseases are less likely to be transmitted to the next generation, and are thus gradually and selectively eliminated from the population through negative selection. Here, we study the determinants of this evolutionary process in genes underlying severe diseases in humans. Results We propose a novel app...
Article
Background: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitr...
Article
Full-text available
Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small...
Article
Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F–dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β–dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an...
Preprint
Humans homozygous or hemizygous for variants predicted to cause a loss of function of the corresponding protein do not necessarily present with overt clinical phenotypes. However, the set of effectively dispensable genes in the human genome has not yet been fully characterized. We report here 190 autosomal genes with 207 predicted loss-of-function...
Article
Full-text available
Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP foll...
Conference Paper
Genome profiling represents a critical pillar for clinical, translational, and basic research studies. Hospitals, core facilities, and research enterprises invest significant resources to generate genomic data sets. Yet, data management and analysis is frequently manual, which demands significant operator time and often results in siloed resources...
Conference Paper
Genome profiling represents a critical pillar for clinical, translational, and basic research studies. Hospitals, core facilities, and research enterprises invest significant resources to generate genomic data sets. Yet, data management and analysis is frequently manual, which demands significant operator time and often results in siloed resources...
Article
Full-text available
Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing o...
Article
Computational analyses of human patient exomes aim to filter out as many nonpathogenic genetic variants (NPVs) as possible, without removing the true disease-causing mutations. This involves comparing the patient’s exome with public databases to remove reported variants inconsistent with disease prevalence, mode of inheritance, or clinical penetran...
Article
Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12–dependent IFN-γ immunity and IL-23–...
Article
Full-text available
Objective Deficiency in the cytosolic DNA sensor RNA Polymerase III (POL III) was recently described in children with severe varicella-zoster virus (VZV) infection in the CNS or lungs. Here, we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and...
Article
Full-text available
Next-generation sequencing (NGS) generates large amounts of genomic data and reveals about 20 000 genetic coding variants per individual studied. Several mutation damage prediction scores are available to prioritize variants, but there is currently no application to help investigators to determine the relevance of the candidate genes and variants q...
Article
Full-text available
Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q in...
Preprint
Deficiency in the cytosolic DNA sensor RNA Polymerase III was recently described in children with severe varicella zoster infection in the CNS or lungs. Here we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation. The clinical presentation and findings included recurrent episo...
Article
Full-text available
Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor...
Article
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and...
Article
JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated....
Article
Myelofibrosis (MF) is a common feature of the Philadelphia-Chromosome negative (Ph-) myeloproliferative neoplasms (MPN), a group that includes Primary Myelofibrosis (PMF), Essential Thrombocytosis (ET) and Polycythemia Vera (PV). Current treatment with Jak2 inhibitors reduces splenomegaly, but does not eliminate malignant clones nor improve bone ma...
Article
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in...
Article
Full-text available
Recent studies have reported that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 occur in myeloid malignancies, and hematopoietic-specific loss of Tet2 induces aberrant hematopoietic stem cell (HSC) self-renewal/differentiation, implicating...
Article
Introduction: The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, which include polycythemia vera, essential thrombocythemia and myelofibrosis. These disorders are characterized by activation of the JAK-STAT pathway via somatic mutations in JAK2, MPL, and CALR. However, a number of...
Article
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Unfortunately, a significant proportion of patients relapse after responding to initial treatment reflecting our poor understanding of the mechanisms mediating therapy resistance and relapse. We hypothesized that understanding the evolution of the mutational landscape...
Article
Cytokine-mediated signal transduction is critical to hematopoiesis, immune responses, and other physiological processes. Aberrant production and secretion of pro-inflammatory cytokines disturbs homeostasis and proper immune function and if persistent results in symptoms of chronic inflammation. Previous studies have illustrated the importance of JA...
Article
Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hema...
Article
Epigenetic modifiers and signaling factors are frequently mutated and often co-occur in various myeloid malignancies. However, precisely how these mutations cooperate to cause myeloid leukemia is not fully understood. Here, we show that cells with concurrent Ten-eleven-translocation 2 (Tet2) loss and Nras mutation can cause lethal chronic myelomono...
Article
Aberrant megakaryopoiesis is a hallmark of the myeloproliferative neoplasms (MPN). It is has been long known that abnormal megakaryocytes secrete elevated levels of cytokines such as TGFβ, resulting in pathologies including bone marrow fibrosis. Two recent studies showed that megakaryocytes regulate the quiescence of HSCs, raising the possibility t...
Article
Acute myeloid leukemia (AML) is a predominantly fatal hematopoietic malignancy with high inter-patient and intra-patient genetic and epigenetic heterogeneity. The prognosis of relapsed AML remains dismal, yet the epigenetic basis of relapse is still unclear. Here we investigated whether and how the epigenome evolution impacts AML progression with b...
Article
Full-text available
Acute myeloid leukemia (AML) is an aggressive malignancy with median age at diagnosis of 67 years,[1][1] stressing the importance of developing treatments that are both effective and tolerable in elderly patients. Hypomethylating agents (HMAs) have been extensively studied in AML, typically in older
Article
Full-text available
We examined the genetic implications and clinical impact of telomere length (TL) in 67 patients with acute myeloid leukemia (AML). There was a trend toward improved survival at 6 months in patients with longer TL. We found that patients with activating mutations, such as FLT3-ITD, had shorter TL, while those with mutations in epigenetic modifying e...
Article
Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), so...
Article
Full-text available
Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients...
Article
Full-text available
Myeloproliferative neoplasms (MPN) are well-delineated diseases in adults but are rare, poorly understood conditions in children. Essential thrombocytosis (ET), one of the classical BCR-ABL-negative MPN, is overall a rare finding in the pediatric population but seems to be one of the more common MPN reported in children. It occurs less frequently a...
Article
Full-text available
DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here we investigated the impact of conditional hematopo...
Article
Full-text available
t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement for cooperating mutations. To...
Article
Background: Primary testicular diffuse large B cell lymphoma (DLBCL) is an uncommon malignancy portending a poor prognosis with increased risk of central nervous system disease. Phenotypically, most primary testicular lymphomas have a non-germinal center B-cell like (non-GCB) origin. To identify the genetic characteristics of testicular DLBCL, we e...