Clinical and diagnostic relevance of NOTCH2 -and KLF2 -mutations in splenic marginal zone lymphoma

Abstract

Splenic marginal zone lymphoma (SMZL) is a small Bcell lymphoma distinguished by frequent 7q loss and the biased use of IGHV01-02. Massive sequencing techniques have demonstrated NOTCH2 and KLF2 gene mutations to be the most frequent mutations in SMZL, with NOTCH2 mutations occurring in 10-25% of SMZL cases, 1-3 and transcription factor KLF2 mutations present in 12-44% of SMZLs.1,4,5 The clinical impact of NOTCH2 alterations is controversial, with different studies reaching very distinct conclusions.3 Herein, we have analysed NOTCH2 and KLF2 mutations in a large series of SMZLs and examined the associations of these alterations with clinicopathological features. Our results confirm the association of the NOTCH2 mutation with shorter median treatment-free survival and suggest the possible usefulness of the identification of these changes for the diagnosis of SMZL.The study panel comprised a series of 84 SMZL patients, and, for comparison purposes, 76 non-SMZL B-cell lymphomas, including 12 splenic diffuse red pulp B-cell lymphoma (SDRPL), 13 chronic lymphocytic leukemia (CLL), 14 mantle cell lymphoma (MCL), 14 follicular lymphoma (FL), 1 hairy cell leukemia (HCL) and 18 lymphoplasmacytic lymphoma (LPL). Four cases of monoclonal B-cell lymphocytosis (MBL) with non-CLL phenotype were also included. The diagnosis of all the lymphoma types included in the series was performed according to WHO criteria and Matutes et al. 6,7 MBL cases had a B-cell monoclonal population without lymphadenopathy or splenomegaly.The NOTCH2 C-terminal coding exon 34 and the KLF2

Systematic Review of Somatic Mutations in Splenic Marginal Zone Lymphoma

“…Six discovery genome wide studies 1–6 implemented WGS or WES with an unbiased approach and subsequently confirmed the variants using targeted sequencing. The nine extension/confirmation studies 1,2,4,6–10,12 were hypothesis based, targeting pathways identified in discovery cohorts or validation of recurrently mutated genes. Three comparison studies 11,13,14 sequenced SMZL cases as reference points to compare other B-cell lymphomas.…”

Human marginal zone B cell development from early T2 progenitors

“…KLF2 drives follicular B cell maturation in mice and its deletion results in an expansion of MZB cells. The role of KLF2 in human B cell development is not known; however, loss-of-function KLF2 mutations along with NOTCH2 mutations that increase the stability of the notch intracellular domain are the most commonly encountered mutations in human MZB cell lymphoma ( Campos-Martín et al, 2017 ). This implicates KLF2 in human B cell fate decisions, suggests a role for IFN-γ in B cell development, and supports its proposed involvement of the imbalance of B cell subsets in LN.…”

Aggressive variant of splenic marginal zone lymphoma characterized using a cancer panel test and treated with rituximab-containing chemotherapy

“…[ 3 ] FATHMM-XF analysis predicted the single nucleotide mutations detected in NCOA4, PTEN, and EPHA3 to be pathogenic (Table 2 ). NOTCH2 is one of the most frequently (10% to 25%) mutated genes in SMZL, [ 12 ] whereas NOTCH2 mutations are not found in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), low grade follicular lymphoma (FL), or hairy cell leukemia (HCL). [ 13 , 14 ] The frameshift/deletion mutation we found in this case affects the C-terminal PEST domain of NOTCH2, which is critical for NOTCH2 proteasomal degradation.…”