Table 1 |.
Oncogenic mechanisms and potential targets in DLBCL subtypes
| DLBCL subtype | Cell of origin | Oncogenic mechanisms | Potential targets |
|---|---|---|---|
| GCB | Germinal centre B-cell |
BCL2 translocation* EZH2 mutations‡ PTEN deletions§ Loss of PTEN expression |
BCL6 EZH2 PI3K/Akt |
| ABC | Post-germinal centre B-cell | NF-κB activation∥ CARD11 mutations MYD88 mutations CD79B mutations A20 deletions |
BCR CBM complex IRAK-4 JAK-STAT |
| PMBL | Post-thymic B-cell | NF-κB activation¶ 9p24 amplification¶ REL amplification JAK2 mutations CIITA translocations# |
JAK-STAT PD-1# |
GCB DLBCL frequently has BCL2 translocations63 and most result in activation of BCL-6, the master transcriptional regulator of the germinal centre.70
Mutations in EZH2 (21% of GCB DLBCL cases) are specific for this subtype.43
Loss of PTEN expression (55% of GCB DLBCL cases)53 results in activation of the PI3K/Akt pathway for which multiple inhibitors are currently in development.
ABC DLBCL is defined by constitutive NF-κB pathway activation75 and BCR signalling pathways are oncogenically activated in this subtype:81 mutations in MYD88, CARD11 and CD79B are found in ABC DLBCL along with deletions and mutations of TNFAIP3.80,82
PMBL is characterized by amplification of chromosome 9p24 and NF-κB pathway activation.136
PDL1 and PDL2 are overexpressed in PMBL22 making their receptor, PD-1, a potential target; recurrent CIITA translocations also result in PD-1 pathway activation in PMBL.141
Abbreviations: ABC, activated B-cell; BCR, B-cell receptor; CBM, CARD11-MALT1-BCL-10; DLBCL, diffuse large B-cell lymphoma; GCB, germinal centre B-cell; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; PMBL, primary mediastinal B-cell lymphoma.