Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

Fält, Susann; Merup, Mats; Tobin, Gerard; Thunberg, Ulf; Gahrton, Gösta; Rosenquist, Richard; Wennborg, Anders

doi:10.1182/blood-2004-10-4073

Cited by 42 publications

(30 citation statements)

References 42 publications

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“…In particular, we observed up-regulation of several genes involved in DNA replication/cell cycle control, transcription and protein kinase activity in IGHV3-21 CLL cases compared to in non-IGHV3-21 CLL cases, indicating a proliferative phenotype, which might account for the more aggressive clinical course. 12 This is in turn supported by the high number of copy number alterations detected in this subset.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 55%

“…4 In a study on global expression profiling, patients with IGHV3-21 had a different gene expression pattern from that of non-IGHV3-21 patients. 12 Genes involved in DNA replication/cell cycle control, transcription and protein kinase activity were found to be differentially expressed, which may lead to a higher rate of proliferation and hence underlie the poor outcome of the patients with IGHV3-21.…”

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confidence: 99%

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Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Marincevic¹,

Mansouri²,

Kanduri³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundNumerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with "stereotyped" B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level. Design and MethodsWe investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays. ResultsAlthough generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients. ConclusionsOur novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.Key words: stereotyped BCR, IGHV4-34, chronic lymphocytic leukemia, gene expression. IGHV4-34 B-cell receptors. Haematologica 2010;95(12):2072-2079. doi:10.3324/haematol.2010 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Marincevic M, Mansouri M, Kanduri M, Isaksson A, Göransson H, Smedby KE, Jurlander J, Juliusson G, Davi F, Stamatopoulos K, and Rosenquist R. Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 55%

mentioning

confidence: 99%

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Marincevic¹,

Mansouri²,

Kanduri³

et al. 2010

Haematologica

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“…[1][2][3][4][5][6][7][8][9][10] Initial studies showed that all B-CLL cases have common features resembling those of a memory B cell. 1,3,11,12 Subsequently, considerable differences in gene expression were linked to various discriminators between good and poor risk B-CLL: these include cytogenetic aberrations, 13,14 expression of the CD38 protein, 15,16 the expression of microRNAs, 17,18 and most importantly, immunoglobulin V H gene (IgV H ) mutational status.…”

Section: Introductionmentioning

confidence: 99%

Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression

et al. 2006

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“…CLL cells are known to have a different distribution of V gene use compared with normal B cells (15). Furthermore, use of certain V genes (e.g., V1-69, V3-21) or even more specific restricted combinations of V(D)J and light chains are independent poor prognostic factors (16,17), with specific types having distinct gene expression patterns (18). It is postulated that this stereotypy results in surface BCR with specific affinity for immunogen capable of tonically stimulating the BCR, thereby promoting cancer cell survival 19,20).…”

Section: Discussionmentioning

confidence: 99%

Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

Blachly

Ruppert

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 10 12 ) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was outof-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL.RNA sequencing | immunoglobulin | somatic hypermutation | B cells | CLL I mmunoglobulins (Igs) are proteins produced by mature B-lymphocytes that recognize foreign antigens, both as soluble antibody molecules and as part of the B-cell receptor. The generation of Ig diversity through gene recombination and hypermutation of the heavy chain (H) variable region (V) is essential to adaptive immunity. The extent of this process is strongly associated with both pathology and prognosis in chronic lymphocytic leukemia (CLL), wherein CLL that expresses an unmutated IGHV tends to be more aggressive than CLL using unmutated IGHV (1, 2). The accurate assessment of this IGHV mutation status is thus of a high clinical priority. As each patient's leukemia generally expresses only a single IGH@, the mutation status of IGHV is determined by amplifying the expressed transcript via RT-PCR, sequencing the gene via the Sanger technique, and then comparing this sequence with known inherited IGHV sequences. However, there are limitations to such methods, including variation in technique across institutions. RNA-sequencing is a powerful technology that can simultaneously yield information about gene and isoform expression as well as underlying DNA sequence (3, 4). Motivated by the notion that a single RNA sequencing experiment could replace many other discrete tests (qPCR, genotyping, microarray, I...

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Distinctive gene expression pattern in VH3-21 utilizing B-cell chronic lymphocytic leukemia

Cited by 42 publications

References 42 publications

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors

Deregulated expression of fat and muscle genes in B-cell chronic lymphocytic leukemia with high lipoprotein lipase expression

Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia

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