IMMUNOGLOBULIN CLASS DICTATES TRANSFORMATION TRAJECTORY AND BCR STATUS OF MYC/BCL2 DOUBLE‐HIT LYMPHOMA: BIOLOGY AND CLINICAL IMPLICATIONS

B cell receptor (BCR) critically contributes to the growth of multiple types of mature B cell neoplasms, representing a preferred target of therapy. In aggressive B-cell non-Hodgkin lymphomas expressing BCL2 and MYC oncoproteins, BCR status remains elusive. Immunohistochemical screening for immunoglobulin (Ig) heavy (H) chains IgM/D/G/A in 331 real-world Diffuse Large B Cell Lymphomas (DLBCL) identified 65% (58/89) of Double-hit (DH) and Triple-hit (TH) lymphomas, carrying MYC/BCL2 (MB2) chromosomal rearrangements, which lacked measurable IgH levels. DHL/THL with undetected IgH (IgHUND) accumulated damaging mutations within Ig variable region genes, presented poor T-cell infiltration and featured transcriptome and mutational profiles sustaining a germinal center (GC) dark zone (DZ)-like molecular program. Conversely, IgH+ MB2 DHL/THL were closely related to GC late centrocytes, embedded within an immune-rich microenvironment, permeated by immunosuppressive cytotypes and cytokines, and sustained by mutational signatures evoking active cross-talk with the tumor niche. Strikingly, whereas IgH+ DHL/THL GCB lymphomas retained IgM expression, IgHUND lymphomas systematically completed IgH class-switching, yet failed to assemble signaling-competent Ig/CD79B/A BCR complexes. Analyses of metachronous specimens representative of the evolution of Follicular Lymphoma into DHL/THL revealed that the IgHUND status, linked to Ig switching, is established in the FL malignant clone and conserved throughout histological transformation. Our data assign to pre- and post-switched Igs distinctive roles in shaping the transformation trajectory of GC B cells upon consecutive acquisition of BCL2 and c-MYC rearrangements, to ultimately become DHL. In particular, isotype-switched Igs confer to GC DZ B cells highest susceptibility to undergo MYC/BCL2-driven transformation under conditions of chronic BCR silencing. Recurrent BCR downmodulation in DHL/THL and other GC-derived DLBCL urges for IgH assessment in routine diagnostics to select patients who will benefit most from emerging anti-CD79B immunotherapies, while directing those with IgHUND lymphomas to alternative treatments. The research was funded by: The Italian Association for Cancer Research (AIRC) Italian Ministry for Education, University and Research through the call for Research Projects of National Relevance Keywords: aggressive B-cell non-Hodgkin lymphoma, microenvironment, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.