Disease-specific mutations in mature lymphoid neoplasms: recent advances.
Detecting these mutations is highly valuable in diagnosing MLN subtypes.Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies.In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies.
Affiliation: Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan; Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.
- Burkitt Lymphoma/genetics*
- Leukemia, Hairy Cell/genetics*
- Leukemia, Large Granular Lymphocytic/genetics*
- Lymphoma, T-Cell/genetics*
- Waldenstrom Macroglobulinemia/genetics*
- High-Throughput Nucleotide Sequencing
- Inhibitor of Differentiation Proteins/genetics
- Janus Kinase 3/genetics
- Myeloid Differentiation Factor 88/genetics
- Neoplasm Proteins/genetics
- Proto-Oncogene Proteins B-raf/genetics
- Receptor, Notch2
- STAT3 Transcription Factor/genetics
- rhoA GTP-Binding Protein/genetics
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fig01: Disease-specific mutations in B-cell lymphoid neoplasms. V-raf murine sarcoma viral oncogene homolog B (BRAF) is a serine/threonine protein kinase that mediates the MAPK pathway. B-cell receptor signaling triggers activation of BRAF. Activated BRAF phosphorylates MEKs, which, in turn, leads to activation of ERKs. The V600E BRAF mutant in hairy cell leukemia possesses constitutive kinase activity, resulting in overactivation of downstream targets. Myeloid differentiation primary-response gene 88 (MYD88) is an adaptor protein that plays an essential role in signaling by the Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R). On cell stimulation, MYD88 is directly recruited to the Toll/IL-1R (TIR) domain in TLRs/IL-1R, binds to Bruton tyrosine kinase (BTK) and acts to recruit IL-1R-associated protein kinases. This leads to activation of the nuclear factor-κB (NF-κB) signaling. The L265P MYD88 mutant in Waldenström macroglobulinemia contributes to constitutive activation of the NF-κB signaling by preferential binding to BTK. Inhibitor of DNA binding (ID3) is a member of the Id helix–loop–helix proteins, which lack a DNA-binding region and function as dominant negative antagonists of basic helix–loop–helix transcription factors, including transcription factor 3 (TCF3). TCF3 plays a role in germinal center B-cell development and promotes cell growth by activating the B-cell receptor signaling pathway, phosphatidylinositol 3-kinase (PI3K) signaling pathway, and positive cell cycle regulator cyclin D3 (CCND3). Gain-of-function mutations in TCF3 and loss-of-function mutations in ID3, the negative regulator of TCF3, in Burkitt lymphoma enhance the TCF3 pathway. NOTCH2 is a single transmembrane receptor. Following NOTCH ligand binding, NOTCH receptor is cleaved in the transmembrane region, resulting in the release of the intracellular domain (ICD) from the plasma membrane. Then ICD is translocated to the nucleus, and activates the transcription of target genes. This signal is terminated by phosphorylation (P) of the proline, glutamate, serine, and threonine (PEST) domain of the ICD, followed by proteasomal degradation. NOTCH2 mutants in splenic marginal zone lymphoma lack the degradation signals in the PEST domain and act in a gain-of-function manner. AKT, v-akt murine thymoma viral oncogene homolog; BCL10, B-cell lymphoma 10; BLNK, B-cell linker; CARD11, caspase recruitment domain family, member 11; ECD, extracellular domain; IKK, IκB kinase; IRAK, I interleukin-1 receptor-associated kinase; MALT1, mucosa associated lymphoid tissue lymphoma translocation gene 1; MAML1, mastermind-like 1; MDM2, MDM2 oncogene, E3 ubiquitin protein ligase; mTOR, mammalian target of rapamycin; MZB, marginal zone B cell; PLCγ, phospholipase C, gamma; PTEN, phosphatase and tensin homolog; RAS, rat sarcoma viral oncogene homolog; RASGRP, RAS guanyl releasing protein; RBPJk, recombination signal binding protein for immunoglobulin kappa J region; SFK, Src family kinases; SHP1, Src homology region 2 domain-containing phosphatase-1; SYK, spleen tyrosine kinase; TAB, TAK1 binding protein; TAK, TGF beta-activated kinase; TIRAP, TIR adaptor protein; TRAF6, TNF receptor-associated factor 6; Ub, ubiquitin.
The BRAF gene encodes a serine/threonine kinase targeting the MAPK signaling cascade. The V600E BRAF mutant is a constitutively active kinase. This mutant causes hyperphosphorylation of MEK1/2, a direct target of BRAF, and ERK1/2, substrates of MEK in HCL cells (Fig.1).5