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.

Center for Novel Therapeutics Moores Cancer Center University of California San Diego La Jolla CA United States

Chronic Lymphocytic Leukemia Center Dana Farber Cancer Institute Boston MA United States

Clinical Hematology Belfast City Hospital Belfast Ireland

Department of Biological Hematology Hôpital Pitié Salpêtrière Sorbonne Université Paris France

Department of Data Science Dana Farber Cancer Institute Boston MA United States

Department of Hematology and Oncology Niguarda Cancer Center Niguarda Hospital Milan Italy

Department of Hematology Royal Bournemouth Hospital Bournemouth United Kingdom

Department of Internal Medicine Hematology and Oncology and Department of Medical Genetics and Genomics University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati OH United States

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Molecular Medicine Donald and Barbara Zucker School of Medicine at Hofstra Northwell Uniondale NY United States

Department of Molecular Pathology Royal Bournemouth Hospital Bournemouth United Kingdom

Departments of Medicine Donald and Barbara Zucker School of Medicine at Hofstra Northwell Uniondale NY United States

Division of Experimental Oncology IRCCS Ospedale San Raffaele Milan Italy

Division of Hematology Mayo Clinic Rochester MN United States

Hematology Department Nikea General Hospital Pireaus Greece

Hematology Unit Department of Medicine University of Padua University Hospital Padua Italy

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

Karches Center for Oncology Research The Feinstein Institutes for Medical Research Northwell Health Manhasset NY United States

Laboratory Medical Immunology Department of Immunology Erasmus MC University Medical Center Rotterdam Netherlands

Northwell Health Cancer Institute Lake Success NY United States

The Robert S Boas Center for Genomics and Human Genetics The Feinstein Institutes for Medical Research Northwell Health Manhasset NY United States

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