Point Mutation Specific Antibodies in B-Cell and T-Cell Lymphomas and Leukemias: Targeting IDH2, KRAS, BRAF and Other Biomarkers RHOA, IRF8, MYD88, ID3, NRAS, SF3B1 and EZH2

Abstract

B-cell and T-cell lymphomas and leukemias often have distinct genetic mutations that are diagnostically defining or prognostically significant. A subset of these mutations consists of specific point mutations, which can be evaluated using genetic sequencing approaches or point mutation specific antibodies. Here, we describe genes harboring point mutations relevant to B-cell and T-cell malignancies and discuss the current availability of these targeted point mutation specific antibodies. We also evaluate the possibility of generating novel antibodies against known point mutations by computationally assessing for chemical and structural features as well as epitope antigenicity of these targets. Our results not only summarize several genetic mutations and identify existing point mutation specific antibodies relevant to hematologic malignancies, but also reveal potential underdeveloped targets which merit further study.

ct-DNA is useful to diagnose mutations at codon 641 of exon 16 of EZH2, which is a biomarker for relapse in patients with Diffuse Large B-cell Lymphoma treated with the R-CHOP scheme.

“…However, within the GC-subtype, some patients show Myc rearrangement with co-expression of BCL2 or BCL6, de ned as double or triple hit lymphomas [2)] which have a more aggressive clinical behavior. Recently, the presence of EZH2 mutations has also been implicated in the prognosis of DLBCL [4][5][6].…”

“…However, within the GC-subtype, some patients show Myc rearrangement with co-expression of BCL2 or BCL6, de ned as double or triple hit lymphomas [2)] which have a more aggressive clinical behavior. Recently, the presence of EZH2 mutations has also been implicated in the prognosis of DLBCL [4][5][6].The epigenetic regulator EZH2 is a subunit of the polycomb repressive complex 2 (PRC2), methylates H3K27, resulting in transcriptional silencing [7][8]. The overexpression of EZH2 has been identi ed as a driver in lymphomagenesis [9].…”

Mutations at Codon 641 of Exon 16 of EZH2 in Circulating Tumor DNA: A Biomarker for Relapse in Patients With Diffuse Large B-cell Lymphoma Treated With the R-CHOP Scheme.

“…The overexpression of EZH2 has been identi ed as a driver in lymphomagenesis [9]. In addition, the mutation at Y646 amino acid in the EZH2 gene is recurrently and signi cantly mutated in up to 40% of B-cell lymphomas [10], and particularly in approximately 13-22% of DLBCL [4,[11][12]. The mutations of Tyr641 (Y641F, Y641N, Y641S, and Y641H) are de cient catalysts of unmodi ed H3K27 methylation relative to the wild type (wt) enzyme.…”

“…However, within the GC-subtype, some patients show Myc rearrangement with co-expression of BCL2 or BCL6, de ned as double or triple hit lymphomas [2)] which have a more aggressive clinical behavior. Recently, the presence of EZH2 mutations has also been implicated in the prognosis of DLBCL [4][5][6].…”

KRAS is a prognostic biomarker associated with diagnosis and treatment in multiple cancers

“…Homozygous deletions of KRAS are the most frequent genetic alteration in pancreatic epithelial adenocarcinoma (PDAC), which results in cell metastasis and the transformation of cancer tumors ( Chang et al, 2014 ). The proto-oncogenes are closely related to multiple cancers, such as cardio-facio-cutaneous syndrome ( Niihori et al, 2006 ), ductal carcinoma of the pancreas ( Hartman et al, 2012 ), leukemias ( Singh et al, 2021 ), mucinous adenoma ( Hartman et al, 2012 ), and noonan syndrome ( Ando et al, 2021 ). The sequences of mutations in KRAS affect the function of genes, oncogenes, tumor-suppressor genes and stability genes and are the critical element for tumorigenesis ( Vogelstein and Kinzler, 2004 ).…”