Proposed model of molecular pathogenesis in the development and progression of major subtypes of MCL. Precursor B cells usually with but sometimes without a CCND1 rearrangement mature to abnormal naïve B cells which may initially colonize, often the inner p... Proposed model of molecular pathogenesis in the development and progression of major subtypes of MCL. Precursor B cells usually with but sometimes without a CCND1 rearrangement mature to abnormal naïve B cells which may initially colonize, often the inner portion of the mantle zones, representing ISMCN. These cells already have additional molecular genetic abnormalities, such as inactivating ATM mutations. They may progress to classical MCL which most frequently is SOX11+, has no evidence of transit through the germinal center, and is genetically unstable acquiring additional abnormalities related to cell cycle dysregulation, the DNA damage response pathway, cell survival, and other pathways. Ultimately, progression to blastoid or pleomorphic MCL may occur. A smaller proportion of neoplastic mantle cells may undergo somatic hypermutation, presumably in germinal centers, leading to SOX11− MCL that are more genetically stable for long periods of time and which preferentially involve the PB, bone marrow (BM), and sometimes the spleen. Even these MCL, however, may undergo additional molecular/cytogenetic abnormalities, particularly TP53 abnormalities, leading to clinical and sometime morphological progression. Adapted from Jares et al31 and Swerdlow et al.2 Professional illustration by Patrick Lane, ScEYEnce Studios. Steven H. Swerdlow et al. Blood 2016;127:2375-2390 ©2016 by American Society of Hematology