TABLE 1.
Pathway-based therapeutically oncogenic biomarkers and their biological characteristics in lymphomas
| Oncogenic Biomarker |
Gene and Location |
Related Signaling Pathways |
Typically Upstream or Downstream Targets |
Protein Description |
Biological Functions | Oncogenic Modes | Mainly Involved Lymphoma Types |
|---|---|---|---|---|---|---|---|
| BCL2 | BCL2, 18q21.33 | Apoptosis pathway | p53, BAD, BAX, BAK, CDK1 | Anti-apoptotic protein | Suppresses apoptotic death | Translocation, amplification, overexpression | FL, DLBCL |
| Myc | MYC, 8q24.21 | Apoptosis pathway | CyclinD1, CyclinD2, CDK4, CDK6, BLIMP-1, MAX, p27KIP1, p21, p14ARF, SMAD3 | Proto-oncogene protein, pleiotropic transcription factor | Involves in cell cycle progression, apoptosis and cellular transformation | Translocation, overexpression, mutation | BL, DLBCL |
| p53 | TP53, 17p13.1 | Intrinsic apoptosis pathway | p14ARF, MDM2, ATM, ATR, p21, chk1, PUMA, NOXA, BAX | Nuclear transcription factor | Regulates transcription; Regulates cell cycle; induces growth arrest or apoptosis | Muatation, inactivation | MCL, CLL/SLL, BL, DLBCL, PMBL, HL |
| BTK | BTK, Xq22.1 | BCR, NF-kB, TLR, cytokine receptor signaling pathway | LYN, SYK, PLCγ2, PKCβ, MYD88, TLR8, TLR9 | Cytoplasmic tyrosine kinase | Modulates B-cell development, immune function, transcription, and apoptosis | Aberrant activation | CLL/SLL, ABC-DLBCL, FL, MCL, MZL |
| SYK | SYK, 9q22.2 | BCR, NF-kB, TCR, IL-2 signaling, PI3K pathway | BTK, SHP-1, BLNK, IKZF1, ROS, PLCγ1, STAT3 | Cytoplasmic non-receptor type tyrosine kinase | Regulates B-cell differentiation, T cells differentiation, adaptive immunity, cell adhesion, and vascular development | Aberrant activation | CLL/SLL, DLBCL, FL, MCL |
| PI3Kδ | PIK3CD, 1p36.22 | PI3K/AKT/mTOR, BCR, apoptosis, NF-kB pathway, JAK/STAT pathway | PIP3, AKT1, N-Ras, H-Ras, K-Ras, PI3K | Serine/threonine protein kinase | Involves in cell growth, proliferation, survival, and morphology | Mutation | DLBCL, FL, MCL |
| PI3Kγ | PIK3CG, 7q22.3 | PI3K/AKT/mTOR, BCR, TLR/MYD88 pathway | PIP3, AKT1, N-Ras, H-Ras | Serine/threonine protein kinase | Involves in B-cell, T-cell, and NK cell development, proliferation, migration, and cytokine production | Aberrant activation | B-cell lymphoma and T-cell lymphoma |
| AKT1 | AKT, 14q32.33 | PI3K/AKT/mTOR, BCR, apoptosis, JAK/STAT pathway, NF-KB pathway | PI3Kδ, MDM2, BAD, FOXO, Raf1 | Serine/threonine protein kinase | Regulates cell survival, growth, proliferation, and angiogenesis | Mutation, overexpression | DLBCL, MCL, PTCL |
| mTOR | MTOR, 1p36.22 | PI3K/AKT/mTOR, BCR, apoptosis, JAK/STAT, NF-KB pathway | AKT1, MAPKAP1, RPS6KB1, RPS6KB2, STAT1, STAT3 | Serine/threonine protein kinase | Regulates cellular metabolism, survival, growth; mTORC1 regulates mRNA translation, protein synthesis, and autophagy; mTORC2 regulates cell survival and cytoskeleton organization | Aberrant activation | CLL/SLL, DLBCL, FL, MCL, and other aggressive lymphoma |
| PTEN | PTEN, 10q23.31 | PI3K/AKT/mTOR, BCR, p53 pathway | miRNA17-92, AKT1, STAT5, PI3K | Tumor suppressor | Negatively modulates cell cycle progression, cell survival, proliferation, and migration | Mutation, inactivation | GCB-DLBCL, MCL, PTEN-deficient lymphomas |
| STAT3 | STAT3, 17q21.2 | JAK/STAT, EGFR, PI3K/AKT pathway, | EGFR, STAT1, Myc, mTOR, CyclinD1, JAK1, JAK2, TYK2, Src | Signal transducer and activator of transcription | Involves in cell growth and apoptosis | Mutation | NK/T cell lymphoma, cutaneous T-cell lymphoma, ALK+ALCL |
| STAT6 | STAT6, 12q13.3 | JAK/STAT pathway, IL-4 signaling pathway | JAK1, JAK2, MAPK8, SHP-1 | Signal transducer and activator of transcription | Activates transcription, involves in IL-4 signaling, induces antiapoptotic activitity | Mutation | PMBL, FL |
| JAK2 | JAK2, 9p24.1 | JAK/STAT pathway, IFNγ signaling pathway | STAT6, SOCS-1, SOCS-3, STAT1, STAT3, IL-6R, IFNγR1, EZH2, SHP-1 | Nonreceptor tyrosine kinase | Involves in cell growth, development, and differentiation; mediates adaptive and innate immunity | Amplification, overexpression, JAK2/SEC31A fusion, JAK2/PCM1 fusion, JAK2/FLT3 fusion | cHL, FL, DLBCL, PMBL, T-cell lymphoma |
| JAK3 | JAK3, 19p13.11 | JAK/STAT pathway, IL signaling pathway | CyclinD3, STAT3, STAT5, IL-2R, IL-6R, BCL2, IRF4, Myc, SHP-1 | Nonreceptor tyrosine kinase | Involves in cell growth, development, and differentiation; mediates adaptive and innate immunity | Mutation | NK/T cell lymphoma, ATLL |
| MYD88 | MYD88, 3p22.2 | IL-1 signaling, TLR, NF-kB pathway | TRAF6, TLR4, IL-1R1, NFKB2, IRAK2, IRAK4, CREBBP, EP300 | Cytosolic adapter protein | Involves in innate and adaptive immunity | MYD88 L256 mutation | LPL/WM, ABC-DLBCL, PCNSL |
| IL-6 | IL6, 7p15.3 | JAK/STAT, PI3K/AKT, and RAS/MAPK pathway | IL-6R, IL6ST | Pleiotropic cytokine | Functions in inflammation and B-cell maturation | Aberrant activation | B-NHL, Castleman’s disease |
| PD-1 | PDCD1, 2q37.3 | Immune system pathway, TCR pathway | PD-L1, PD-L2, SHP-2, | Cell surface membrane protein of the immunoglobulin superfamily receptor | Negatively regulates effector T-cell functions | Overexpression in infiltrating T-cells | FL, CLL/SLL |
| PD-L1 | CD274, 9p24.1 | Immune system pathway, TCR pathway | PD-1 | Immune inhibitory receptor ligand | Inhibits T-cell activation and cytokine production upon interaction with PD-1 | Amplification, overexpression | cHL, PMBL, ABC-DLBCL, ALK+ALCL |
| PD-L2 | PDCD1LG2, 9p24.1 | Immune system pathway, TCR pathway | PD-1 | Immune inhibitory receptor ligand | Inhibits T-cell activation and cytokine production upon interaction with PD-1 | Amplification, overexpression | cHL |
ABC, active B cell; AKT, v-akt murine thymoma viral oncogene homolog1; ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; BCR, B-cell receptor; BL, Burkitt lymphoma; BTK, bruton tyrosine kinase; cHL, classical Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; GCB, germinal center B cell; HL, Hodgkin lymphoma; IL-6, interleukin 6; JAK, Janus kinase; LPL, Lymphoplasmacytic Lymphoma; MALT, mucosa associated lymphoid tissue lymphoma; MCL, mantle cell lymphoma; MDM2, mouse double-minute 2 protein; mTOR, mechanistic target of Rapamycin; mTORC, mTOR complex; MYC, v-Myc avian myelocytomatosis viral oncogene homolog; MYD88, myeloid differentiation primary response 88; MZL, marginal zone lymphoma; NF-κB, nuclear factor-kappaB; NHL, non-Hodgkin’s lymphoma; PCNSL, primary central nervous system lymphoma; PD-1, programmed death-1; PD-Ls, programmed death-ligands; PI3K, phosphoinositide-3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKCβ, protein kinase C β; PMBL, primary mediastinal B-cell lymphoma; PTEN, phosphatase and tensin homolog; SHP, Src homology region 2 domain-containing phosphatase; SLL, small lymphocytic lymphoma; STAT, signal transducer and activator of transcription; SOCS, suppressor of cytokine signaling; SYK, spleen-associated tyrosine kinase; TCR, T-cell receptors; TLR, Toll-like receptors; WM, Waldenstrom’s macroglobulinemia.