B cell M-CLL clones retain selection against replacement mutations in their immunoglobulin gene framework regions

Hadas Neuman, Jessica Arrouasse, Ohad Benjamini, Ramit Mehr*, Meirav Kedmi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Introduction: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, accounting for 30–40% of all adult leukemias. The dynamics of B-lymphocyte CLL clones with mutated immunoglobulin heavy chain variable region (IgHV) genes in their tumor (M-CLL) can be studied using mutational lineage trees. Methods: Here, we used lineage tree-based analyses of somatic hypermutation (SHM) and selection in M-CLL clones, comparing the dominant (presumably malignant) clones of 15 CLL patients to their non-dominant (presumably normal) B cell clones, and to those of healthy control repertoires. This type of analysis, which was never previously published in CLL, yielded the following novel insights. Results: CLL dominant clones undergo – or retain – more replacement mutations that alter amino acid properties such as charge or hydropathy. Although, as expected, CLL dominant clones undergo weaker selection for replacement mutations in the complementarity determining regions (CDRs) and against replacement mutations in the framework regions (FWRs) than non-dominant clones in the same patients or normal B cell clones in healthy controls, they surprisingly retain some of the latter selection in their FWRs. Finally, using machine learning, we show that even the non-dominant clones in CLL patients differ from healthy control clones in various features, most notably their expression of higher fractions of transition mutations. Discussion: Overall, CLL seems to be characterized by significant loosening – but not a complete loss – of the selection forces operating on B cell clones, and possibly also by changes in SHM mechanisms.

Original languageEnglish
Article number1115361
JournalFrontiers in Oncology
StatePublished - 2023


  • B lymphocytes
  • antibody
  • chronic lymphocytic leukemia (CLL)
  • high-throughput sequencing (HTS)
  • immunoglobulin (Ig)
  • lineage trees
  • machine learning (ML)
  • somatic hypermutation (SHM)


Dive into the research topics of 'B cell M-CLL clones retain selection against replacement mutations in their immunoglobulin gene framework regions'. Together they form a unique fingerprint.

Cite this