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B cell M-CLL clones retain selection against replacement mutations in their immunoglobulin gene framework regions
Hadas Neuman1, Jessica Arrouasse1, Ohad Benjamini2,3
1The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
Insights
Chronic lymphocytic leukemia (CLL) exhibits altered B cell clone dynamics due to weakened selection forces on mutations. Non-dominant B cells in CLL patients also show distinct mutation patterns compared to healthy individuals.
Area of Science:
- Hematology
- Immunology
- Genetics
Background:
- Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia.
- Understanding B-lymphocyte clone dynamics in CLL is crucial for disease management.
Purpose of the Study:
- To investigate somatic hypermutation (SHM) and selection in CLL B-cell clones using lineage tree analysis.
- To compare dominant (malignant) CLL clones with non-dominant (normal) B cells within patients and with healthy controls.
Main Methods:
- Lineage tree-based analysis of SHM and selection.
- Comparison of dominant CLL clones, non-dominant B cells from CLL patients, and B cells from healthy controls.
- Machine learning to identify distinct mutational features.
Main Results:
- CLL dominant clones accumulate more replacement mutations affecting amino acid properties.
- CLL clones show weaker selection for/against mutations in complementarity determining regions (CDRs) and framework regions (FWRs) compared to controls.
- Non-dominant CLL B cells exhibit higher transition mutation fractions than healthy controls.
Conclusions:
- CLL is associated with a relaxation, not complete loss, of selection forces on B cell clones.
- Altered SHM mechanisms may also contribute to CLL pathogenesis.
- Distinct mutational profiles in non-dominant B cells suggest broader B-cell dysregulation in CLL.
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.
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