Table 1.
Pathway-related biomarkers and their clinical utilities in lymphoid malignancies.
| Oncogenic biomarkers | Related signaling pathways | Functions | Clinical utilities | Targeted agents | Diseases applied | Detection approaches |
|---|---|---|---|---|---|---|
| BTK | BCR, NF-κB signaling pathway | Modulates B-cell development, immune function, transcription, and apoptosis | Therapeutic | BTK inhibitor: Ibrutinib (PCI-32765), BGB-3111, AVL-292 cc-292, M7583, Acalabrutinib (ACP-196) | CLL/SLL, R/R MCL, ABC-DLBCL, FL, MZL, T-cell lymphoma | Sequencing, PCR, IHC |
| MYD88 | NF-κB, IL-1, TLR signaling pathway | Acts as a signal transducer in the IL-1, IL-18, and TLR signaling pathways; involves in innate and adaptive immunity | Diagnostic: MYD88L256P mutation for LPL/WM, HCL; prognostic: ABC-DLBCL | TLRs ligands inhibitor: IMO-8400; IRAK4 inhibitor; ND-2158, ND-2110 | ABC-DLBCL with MYD88L256P mutation, other malignancies harboring aberrant MYD88, LPL/WM | Sequencing, PCR, IHC |
| CD30 | NF-κB pathway | Diagnostic and differential diagnostic: CD30 overexpression in cHL, ALCL; Therapeutic | Anti-CD30 antibody: Brentuximab vedotin | cHL and ALCL | IHC | |
| PI3Ks | PI3K/AKT/mTOR, BCR, TLR/MYD88 pathway | PI3Kδ involves in cell growth, proliferation, survival, and morphology; PI3Kγ involves in B-cell, T-cell, and NK cell development, proliferation, migration, and cytokine production | Therapeutic | PI3K inhibitor: SAR 245408 (XL147); PI3Kδ/γ inhibitor: Duvelisib (IPI-145, INK1197); PI3Kδ inhibitor: Idelalisib (CAL-101, GS-1101), AMG 319, Acalisib (GS-9820) (CAL-120); PI3Kγ inhibitor: Buparlisib (BKM120) | R/R NHL, advanced hematologic malignancies | Sequencing, PCR, IHC |
| AKT | PI3K/AKT/mTOR, BCR, TLR/MYD88 pathway | Regulates cell survival, growth, proliferation, and angiogenesis | Prognostic and predictive: abnormal phosphorylated-AKT expression; Therapeutic | Akt inhibitor: Perifosine (KRX-0401), MK-2206, GSK690693 | Hematologic malignancies, Lymphomas | IHC, Sequencing, PCR |
| mTOR | PI3K/AKT/mTOR, BCR, TLR/MYD88 pathway | Regulates cellular metabolism, survival, growth; mTORC1 regulates mRNA translation, protein synthesis, and autophagy; mTORC2 regulates cell survival and cytoskeleton organization | Therapeutic | mTOR inhibitor: Temsirolimus (CCI-779), Rapamycin (Sirolimus), Ridaforolimus (AP23573, MK-8669); mTORC1/mTORC2 inhibitor: Everolimus (RAD001), AZD2014 | Lymphoma, multiple myeloma, hematologic malignancies | Sequencing, PCR, IHC |
| BCL2 | Apoptosis pathway | Suppresses apoptotic death | Diagnostic: Overexpression and translocation in FL, double-expression or double-hit lymphoma; amplification in ABC-DLBCL; Therapeutic | BCL2 inhibitor: Venetoclax (ABT199), Obatoclax Mesylate (GX15-070MS) | FL, DLBCL, R/R lymphoid malignancies | IHC, ISH, PCR, sequencing |
| p53 | Apoptosis pathway | Regulates transcription; regulates cell cycle; induces growth arrest or apoptosis | Diagnostic: overexpression or TP53 mutation; Therapeutic | MDM2 inhibitor: APG-115, DS-3032 | Advanced solid tumors or lymphomas | IHC, PCR, sequencing |
| Myc | Apoptosis pathway | Involves in cell cycle progression, apoptosis and cellular transformation | Diagnostic and prognostic: Overexpression and translocation in BL, double-expression or double-hit lymphoma; Therapeutic | BET inhibitor: JQ1, CPI-0610, AZD5153, AZD5153; Aurora A inhibitor: Alisertib; c-Myc-Max dimerization inhibitor: 10058-F4 | BL, DLBCL, hematologic malignancies | IHC, ISH |
| PD-1 | Immune system pathway, TCR pathway | Negatively regulates effector T-cell functions | Predictive: overexpression; diagnostic: expression pattern in AITL; Therapeutic |
Anti-PD-1 antibody: Pidilizumab (CT-011), Nivolumab (BMS-936558, MDX-1106, ONO-4538), Pembrolizumab (lambrolizumab, MK-3475) | Aggressive B-cell lymphomas; advanced malignancies; T-cell or NK-cell lymphomas | IHC, ISH |
| PD-L1 | Immune system pathway, TCR pathway | Inhibits T-cell activation and cytokine production upon interaction with PD-1 | Predictive: overexpression; Therapeutic | Anti-PD-L1 antibody: Durvalumab (MEDI4736), Avelumab (MSB0010718C), Atezolizumab (MPDL3280A) (RG7446) | Lymphomas, solid tumors; Advanced cHL; R/R PTCL | IHC, ISH |
| JAKs | JAK/STAT pathway | Involves in cell growth, development, and differentiation; mediates adaptive and innate immunity | Diagnostic: JAK2/SEC31A fusion in cHL; JAK2/PCM1 fusion in T-cell lymphoma; JAK2/FLT3 fusion in cHL, FL, and DLBCL; Aberrant JAK2 and JMJD2C amplification in cHL and PMBL; Therapeutic | JAK3 inhibitor: Tofacitinib (CP-690550); JAK2 inhibitor: Pacritinib (SB1518), Ruxolitinib (INCB018424) | cHL, EBV-related NK/T cell lymphoma; R/R cHL, FL, MCL, and DLBCL; R/R T-cell or NK cell lymphoma, R/R PMBL | ISH, sequencing, PCR, IHC |
| STATs | JAK/STAT pathway | STAT3 involves in cell growth and apoptosis; STAT6 activates transcription, involves in IL-4 signaling, induces anti-apoptotic activity | Therapeutic | STAT3 inhibitor: Pyrimethamine, IONIS-STAT3Rx (ISIS 481464) | Relapsed CLL/SLL; DLBCL, lymphomas, advanced cancers | Sequencing, PCR, IHC |
ABC: active B-cell; ALCL: anaplastic large cell lymphoma; AITL: angioimmunoblastic T-cell lymphoma; AKT: v-akt murine thymoma viral oncogene homolog; BCL2: B-cell leukemia/lymphoma 2; BCR: B-cell receptor; BET: bromodomain and extra-terminal proteins; BL: Burkitt lymphoma; BTK: bruton tyrosine kinase; CD: cluster of differentiation; cHL: classical Hodgkin lymphoma; CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; EBV: Epstein–Barr virus; FL: follicular lymphoma; HCL: Hairy lymphoma; HL: Hodgkin's lymphoma; IHC: immunohistochemistry; IL: interleukin; IRAK4: interleukin-1 receptor associated kinase 4; ISH: in situ hybridization; JAK: Janus kinase; LPL: lymphoplasmacytic lymphoma; MALT: mucosa associated lymphoid tissue lymphoma; MCL: mantle cell lymphoma; MDM2: mouse double minute 2 protein; MM: multiple myeloma; mTOR: mechanistic target of rapamycin; mTORC: mTOR complex; MYD88: myeloid differentiation primary response 88; MZL: marginal zone lymphoma; NF-κB: nuclear factor-kappa B; NHL: non-Hodgkin's lymphoma; NK: natural killer; PCNSL: primary central nervous system lymphoma; PCR: polymerase chain reaction; PD-1: programmed death-1; PD-Ls: programmed death-ligands; PI3K: phosphoinositide-3-kinase; PMBL: primary mediastinal B-cell lymphoma; PTCL: peripheral T-cell lymphoma; R/R: refractory / relapsed; SLL: small lymphocytic lymphoma; STAT: signal transducer and activator of transcription; TCR: T-cell receptor; TLR: Toll-like receptor; WM: Waldenstrom's macroglobulinemia.