Abstract
Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
| Original language | English |
|---|---|
| Article number | 897280 |
| Journal | Frontiers in Oncology |
| Volume | 12 |
| DOIs | |
| Publication status | Published - 12 Jul 2022 |
Bibliographical note
Funding Information:This study was supported in part by grants from the US National Institutes of Health, National Cancer Institute, PO1-CA81534 and RO1-CA236361 to TK and R01-CA238523 to NC. SP is supported by Ministry of Health of the Czech Republic, grant No. (NV19-03-00091). RR is supported by the Swedish Cancer Society, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, Karolinska University Hospital, and Radiumhemmets Forskningsfonder, Stockholm. KS has received support from the Hellenic Precision Medicine Network in Oncology; and the project ODYSSEAS, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union, with grant agreement no: MIS 5002462. NC and KR thank the Karches Family, The Nash Family Foundation, and the Jean Walton Fund for Leukemia, Lymphoma, and Myeloma Research for their support of the Feinstein Institutes’ CLL Research & Treatment Program.
Funding Information:
The following authors received funding from other sources as listed. However, these funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
Publisher Copyright:
Copyright © 2022 Kaufman, Yan, Li, Ghia, Langerak, Rassenti, Belessi, Kay, Davi, Byrd, Pospisilova, Brown, Catherwood, Davis, Oscier, Montillo, Trentin, Rosenquist, Ghia, Barrientos, Kolitz, Allen, Rai, Stamatopoulos, Kipps, Neuberg and Chiorazzi.
