Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLLSLL)

Overview

CLL/SLL is a Mature B-Cell Neoplasm (parent MBN). IGHV-mutated (M-CLL) and IGHV-unmutated (U-CLL) define major molecular subtypes with distinct driver landscapes and prognoses.

Cohorts in the corpus

  • cll_broad_2022: 1,148 patients (1,095 CLL, 54 MBL); WES/WGS n=1,074 (984 WES, 177 WGS); RNA-seq n=712; DNA methylation n=999 — the largest integrated CLL cohort to date PMID:35927489.

Recurrent alterations

  • Cardinal drivers: SF3B1 17.5%, NOTCH1 12.3%, ATM 11.2%, TP53 9.1% PMID:35927489.
  • 202 candidate drivers (109 novel); 24.2% of patients carry at least one novel driver mutation PMID:35927489.
  • Non-coding/non-standard drivers: IGLV3-21 R110 9.5%, U1 snRNA g.3A>C 3.8% PMID:35927489.
  • Novel drivers via 3D CLUMPS clustering include MAP2K2, DIS3, DICER1, INO80 PMID:35927489.
  • Recurrent SVs: BCL2 translocations predominantly in M-CLL (5.7% of WGS cases) via aberrant V(D)J; recurrent 37-Mb chr14 deletion disrupting ZFP36L1, DICER1, TRAF3 in U-CLL (4.6%) via class-switch recombination PMID:35927489.
  • Mutational signatures: canonical AID (SBS84) enriched in U-CLL; non-canonical AID (SBS85) enriched in M-CLL (p=1.6×10^-9) PMID:35927489.
  • WES of 160 CLL tumors identified SF3B1, NOTCH1, DDX3X, and POT1 as significantly mutated genes; SF3B1 mutations associated with poor prognosis PMID:23415222
  • Genomic profiling of CLL/SLL identified recurrent alterations in SF3B1, NOTCH1, ATM, and TP53; mutational landscape informs prognosis and therapeutic targeting PMID:26200345
  • Genomic analysis of CLL/SLL identified recurrent driver mutations and copy number alterations informing disease prognosis and targeted therapy strategies PMID:26466571

Subtypes

  • IGHV-unmutated CLL (U-CLL, n=459) harbors more drivers than IGHV-mutated CLL (M-CLL, n=512): 54 vs 25 drivers (ratio 2.16, p=0.0015) PMID:35927489.
  • 8 gene-expression clusters identified by unsupervised RNA-seq clustering (n=603 treatment-naive) are independent prognostic factors beyond IGHV/epitype PMID:35927489.
  • Epitype framework (n-CLL, i-CLL, m-CLL) with epiCMIT mitotic clock PMID:35927489.

Therapeutic landscape

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:23415222

This page was processed by crosslinker on 2026-05-14. - PMID:26200345

This page was processed by crosslinker on 2026-05-14. - PMID:26466571

This page was processed by crosslinker on 2026-05-14.