Genetic landscapeof hepatitis B virus-associated diffuse large B-cell lymphoma. Blood 2018View Details
Reduced immunoglobulingene diversity in patients with Cornelia de Lange syndrome. J Allergy Clin Immunol. 2018View Details
Combined immunodeficiencyand Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med. 2017View Details
Common variantsat PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nat Genet. 2016View Details
Genetic basisof PD-L1 overexpression in diffuse large B-cell lymphomas. Blood. 2016View Details
We focus on two main areas of research: Immunogenetics and Cancer Genetics
Regulation of immunoglobulin class switch recombination in human B cells
The project is aimed at understanding the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM) and their involvement in the pathophysiological processes leading to immunodeficiency, genome instability and cancer development in humans.
Induced pluripotent stems cells a platform for personalized diagnosis and therapy in patients with primary immunodeficiency
The project is aimed at reprogramming the fibroblasts or peripheral blood B cells derived from IgA deficient (IgAD) patients into pluripotent stem (iPS) cells and to re-differentiate these iPS cells into antibody-producing B cells. If successful, this study may provide a potentially curative treatment in patients with IgA deficiency. They will also provide a methodological platform for studies aimed at replacing cells in patients with a variety of other primary immunodeficiency diseases as well as autoimmune and neurological disorders associated with these diseases.
Discovery of therapeutic targets in B cell lymphoma by next generation sequencing
The project is aimed at identifying potentially treatable molecular targets in mature B cell lymphomas (with focus on diffuse large B cell lymphomas and mantle cell lymphomas) by high-throughput, next generation-sequencing omic- technologies such as whole genome and exome sequencing and RNA-seq.
Funding and Partners
Our projects are conducted thanks to the support of remarkable funding agencies and partners
of hepatitis B virus-associated diffuse large B-cell lymphoma. Ren W. et al. 2018.
Abstract Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.
gene diversity in patients with Cornelia de Lange syndrome. Björkman A. et al. 2017.
Abstract B-cells rely on a broad receptor repertoire to provide protection against a wide range of pathogens. This is in part achieved via V(D)J recombination which, by assembling various combinations of variable (V), diversity (D) and joining (J) genes, creates different immunoglobulin (Ig) V regions(1). The recombination processes is initiated by RAG1/RAG2 enzymes and requires a functional non-homologous end joining (NHEJ) machinery. B-cells can further diversify their Ig V regions through somatic hypermutation (SHM), to improve the affinity between the antibody and antigen, and switch the isotype of antibody produced by class switch recombination (CSR). Both processes are initiated by activation-induced cytidine deaminase (AID) and rely on transcription and a number of DNA repair mechanisms.
and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. Abolhassani H. et al. 2017.
Abstract In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.
at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Bronson PG. et al. 2016.
Abstract Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10-8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10; AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3+ regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.
of PD-L1 overexpression in diffuse large B-cell lymphomas. Georgiou K. et al. 2016.
Abstract Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.
Prof. Dr. Qiang Pan-Hammarström
Dr. Qiang Pan-Hammarström is a professor of clinical immunology and member of the Nobel Assembly at the Karolinska Institutet. She is also a visiting professor at Sun Yat-Sen University Cancer Centre and Tianjin Medical University Cancer Institute in China.
Dr. Qiang Pan-Hammarström was trained as a medical doctor and graduated from Sun Yat-Sen Medical University in 1993. During 1993 and 1994 she worked as a physician at the Guangzhou Respiratory Disease Research Institute. She obtained her PhD degree in molecular immunology at the Karolinska Institute in 1999 and carried out her postdoc training at Harvard Medical School in 2000. In 2001 she came back to the Karolinska Institutet where she became an associate professor and group leader in 2004. She was a guest professor at Beijing University from 2005 to 2009, a visiting scientist in Harvard Medical School in 2012, a visiting professor at Rockefeller University from 2013-2015, a visiting scientist in the Broad Institute at Harvard and MIT from 2016 to 2017. She was appointed professor of clinical immunology at the Karolinska Institutet in 2011 and was elected into the Nobel Assembly at the Karolinska Institutet in 2019.
Dr. Qiang Pan-Hammarström has published over 115 papers in areas of immunoglobulin gene diversifications, primary immunodeficiencies, genome instability and B cell malignancies.