Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.
Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.
Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.
Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290-300. ©2015 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2123 | DOI Listing |
Hinyokika Kiyo
November 2024
The Department of Urology, Nara Medical University.
A 28-year-old man was diagnosed with chlamydial urethritis by his previous doctor and was prescribed minocycline (MINO). The result of a urinary chlamydia polymerase chain reaction (PCR) test later confirmed to be negative. However, the patient visited our hospital because of persistent miction pain.
View Article and Find Full Text PDFBull Cancer
December 2024
Service d'hématologie, CHU de Poitiers, CIC 1402 Inserm université, 86000 Poitiers, France.
Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells.
View Article and Find Full Text PDFCardiooncology
December 2024
Department of Cardiovascular Medicine, Mayo Clinic, 200 1 St SW, Rochester, MN, 55905, USA.
Background: CD19 CAR T-cell therapy is a novel anti-cancer treatment that has produced remarkable responses in relapsed or refractory B-cell hematological malignancies. Cytokine Release Syndrome (CRS) is a dysregulated immune response that frequently occurs after CAR T-cell infusion. It can cause cardiac dysfunction and circulatory collapse negatively impacting outcomes and survival.
View Article and Find Full Text PDFBioorg Chem
December 2024
Core Facility, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, PR China. Electronic address:
XPO1 is an influential member of the nuclear transporter protein family. The proteins and RNA transported by XPO1 are related to the occurrence and development of many diseases, including refractory tumor diseases and various viral infectious diseases. XPO1 is upregulated in many malignant tumors and is associated with poor prognosis.
View Article and Find Full Text PDFAm J Hematol
December 2024
Department of Hematology, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, Beijing, China.
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