Abnormal B-Cell Maturation and Increased Transitional B Cells in CBL Syndrome

Abstract

CBL syndrome is a Noonan-like RASopathy with heterogeneous clinical phenotype and predisposition to juvenile myelomonocytic leukemia (JMML). Here we describe two patients with identical germline CBL mutation and clinical and immune-hematological overlapping features with autoimmune lymphoproliferative syndrome (ALPS) and B-cell expansion with NF-κB and T-cell anergy (BENTA) syndrome. Increased immature/transitional B cells can be depicted in CBL syndrome, ALPS, and BENTA. Nonetheless, our patients here described showed peculiar B-cell phenotype due to increased immature/transitional CD34+ B cells. This feature differentiates CBL syndrome from BENTA, pointing toward an abnormal proliferation of B-cell early precursors.

Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant

“…By functioning as an adaptor, CBL has also been reported to act as a positive regulator of signaling elicited by RTKs. Extensive studies demonstrated that E3 activation is required for RTKs ubiquitination (Martinelli et al, 2012;Niemeyer et al, 2010;Saettini et al, 2022;Thien et al, 2001). Multiple lines of evidence support the view that RASopathy-and leukemia-associated CBL syndrome is a highly variable condition accounting for <1% of subjects with some clinical features reminiscent of NS (Martinelli et al, 2010(Martinelli et al, , 2015Niemeyer et al, 2010;Pérez et al, 2010).…”

“…By functioning as an adaptor, CBL has also been reported to act as a positive regulator of signaling elicited by RTKs. Extensive studies demonstrated that E3 activation is required for RTKs ubiquitination (Martinelli et al, 2012; Niemeyer et al, 2010; Saettini et al, 2022; Thien et al, 2001). Multiple lines of evidence support the view that RASopathy‐ and leukemia‐associated mutations affect CBL function and RTKs ubiquitination by impairing the E3 catalytic activity of the protein.…”

“…A large fraction of subjects harboring a germline CBL variant experience hematological and immunological problems (Roberts et al, 2013; Saettini et al, 2022). Hepatosplenomegaly, which is generally associated with JMML because of infiltration of leukemic cells into spleen and liver, may occur in CBL syndrome even in the absence of a clear myeloproliferative/myelodysplastic disorder (Ali et al, 2020; Becker et al, 2014; Coe et al, 2017; Leardini et al, 2022).…”