Cells of origin and molecular subtypes of CLL and MCL
| . | CLL* . | MCL* . | |||
|---|---|---|---|---|---|
| IGHV-unmutated . | IGHV-mutated . | Conventional . | Leukemic nonnodal . | ||
| Gene expression24,109 | CD5+CD27−; pre–germinal center cell | CD5+CD27+; post–germinal center cell | Naive B-cell–like | Memory B-cell–like | |
| Germinal center relation, IGHV germ line identity | Unexperienced; IGHV ≥ 98% | Experienced; IGHV < 98% | Unexperienced† | Experienced† | |
| Epigenetic signature25-27 | Naive-like‡ | Intermediate‡ | Memory-like‡ | Naive-like | Memory-like |
| IGHV germ line identity, % (mean ± SD)25,27,109,111 | 99.7 (±1.0) | 96.4 (±2.4) | 92.9 (±3.2) | 98.7 (±2.6)† | 95.1 (±1.5)† |
| IGHV bias25,109,111 | IGHV4-34 | IGHV4-34 | |||
| IGHV1-69 | IGHV3-21 | IGHV4-34 | IGHV5-51 | IGHV5-51 | |
| IGHV4-39 | IGHV1-18 | IGHV3-7 | IGHV3-21 | IGHV1-8 | |
| IGHV3-23 | IGHV4-59 | ||||
| Stereotypes§,21,25,168 | Subsets 1, 6, 8 | Subset 2 | Subsets 4, 16 | ||
| Gene mutations66,116,168,169 | NOTCH1, ATM | SF3B1, ATM | MYD88 | ATM, CDKN2A del | CCND1, TLR2 |
| . | CLL* . | MCL* . | |||
|---|---|---|---|---|---|
| IGHV-unmutated . | IGHV-mutated . | Conventional . | Leukemic nonnodal . | ||
| Gene expression24,109 | CD5+CD27−; pre–germinal center cell | CD5+CD27+; post–germinal center cell | Naive B-cell–like | Memory B-cell–like | |
| Germinal center relation, IGHV germ line identity | Unexperienced; IGHV ≥ 98% | Experienced; IGHV < 98% | Unexperienced† | Experienced† | |
| Epigenetic signature25-27 | Naive-like‡ | Intermediate‡ | Memory-like‡ | Naive-like | Memory-like |
| IGHV germ line identity, % (mean ± SD)25,27,109,111 | 99.7 (±1.0) | 96.4 (±2.4) | 92.9 (±3.2) | 98.7 (±2.6)† | 95.1 (±1.5)† |
| IGHV bias25,109,111 | IGHV4-34 | IGHV4-34 | |||
| IGHV1-69 | IGHV3-21 | IGHV4-34 | IGHV5-51 | IGHV5-51 | |
| IGHV4-39 | IGHV1-18 | IGHV3-7 | IGHV3-21 | IGHV1-8 | |
| IGHV3-23 | IGHV4-59 | ||||
| Stereotypes§,21,25,168 | Subsets 1, 6, 8 | Subset 2 | Subsets 4, 16 | ||
| Gene mutations66,116,168,169 | NOTCH1, ATM | SF3B1, ATM | MYD88 | ATM, CDKN2A del | CCND1, TLR2 |
SD, standard deviation.
Immunogenetic analyses of the BCR in both entities strongly indicate that antigen selection plays an important role in the clonal expansion of all subtypes independently of the cell of origin.
Although the IGHV germ line identity differs significantly between conventional (SOX11+) and leukemic nonnodal (SOX11−) MCL, there is not a clear cutoff to distinguish both subtypes.109
Oakes et al26 identified the same 3 epigenetic CLL subgroups based on the methylation levels of the binding sites of the transcription factors AP-1, EBF1, and RUNX3. They named these subgroups low-, intermediate-, and high-programmed CLL based on the comparison of the changes in CLL with those occurring in normal naive B cells upon stimulation with CD40L and IgM.
Stereotyped BCRs have been detected in ∼30% of CLL and 10% MCL. However, the BCR sequences differ significantly in both diseases.21,109