Review Series AGGRESSIVE B-CELL LYMPHOMAS Mantle cell lymphoma: evolving management strategies

Mantle cell lymphoma (MCL) is genetically characterized by the translocation t(11;14)(q13;q32) and the overexpression of CCND1 that probably facilitates the transformation of the cells by deregulating the cell cycle. This initial event is acquired in pre-B cells of the bone marrow and seems to be followed by 2 different molecular pathways that configure 2 clinical and biological subtypes of the disease. The classical andmost common form ofMCLderive from mature B cells that do not enter the follicular germinal center and carrynoor a limitednumber of IGHV somaticmutations.These tumors express the transcription factor SOX11, are genetically unstable, and tend to accumulate alterations in cell cycle regulatory genes, the DNA damage response pathway, and cell survival mechanisms. The acquisition of these alterations results in a more aggressive behavior. The second less common subtype of MCL is characterized by cells that also carry the t(11,14) and CCND1 overexpression but have experienced the follicular germinal center and carry IGHV with somatic hypermutations. These cells are genetically stable, SOX11 expression is negative or very low, and the tumor tends to disseminate to the peripheral blood and spleenmore than to the lymph nodes. The disease seems to be stable and asymptomatic for long periods of time, but some tumors may acquire additional alterations in genes such as TP53 that lead to the progression of the disease and transformation to a more aggressive variant. The relevance of SOX11 in the pathogenesis of MCLs is highlighted by its negative expression in all mature lymphoid cells and virtually all mature B-cell neoplasms. SOX11 promotes tumor growth of MCL cells in vivo and regulates a broad transcriptional program that includes B-cell differentiation, cell proliferation, apoptosis, and angiogenesis among other oncogenic mechanisms. One of the strongest direct targets of SOX11 is PAX5, a master regulator of B-cell differentiation that is physiologically downregulated in the terminal steps toward plasma cells. The forced expression of PAX5 by SOX11 may prevent the cells from responding to normal differentiation signals, blocking their maturation process. A subset of MCL does not carry the t(11,14) translocation and CCND1 expression but has the same pathological and clinical characteristics of MCLs with this genetic alteration. Intriguingly, 55% of these tumors carry CCND2 translocations and all of them have SOX11 expression, emphasizing the relevance of this transcription factor in the pathogenesis of MCLs. The most common alterations further deregulating cell cycle in MCLs involve the INK4a/CDK4/RB1 and ARF/MDM2/TP53 pathways. The CDKN2A locus (9p21), frequently deleted in MCL, connects both pathways encoding the CDK inhibitor INK4a and the positive p53 regulator ARF. TP53 is commonly mutated gene in MCL (19-28%), and RB1 is also inactivated by point mutations or gene deletions in occasional cases. Gene amplification leads to the overexpression of CDK4, MDM2, and BMI1, which in turn repress theCDKN2A locus. The relevance of cell cycle deregulation inMCL is highlighted by the poor prognosis conferred by high proliferative activity measured either by a gene expression signature or the Ki67 index. Recent genome-wide studies using next-generation sequencing (NGS) have expanded the perspective of genes and pathways involved in the development of MCLs. These studies have confirmed that the most common secondary alteration in MCLs is the mutation of the DNA damage sensor ATM (42-55% of cases), usually associated with 11q deletions and a high number of chromosomal alterations. These alterations seem to accumulate in tumors expressing SOX11. Novel mechanisms identified include activating mutations in NOTCH1/2 in ;10% of the tumors associated with an aggressive evolution. Mutations in several chromatin modifiers such as WHSK1 (10%), MLL2 (14%), and MEF2B (3%) have also been detected almost exclusively in MCLs expressing SOX11. WHSK1 mutations seem to deregulate a set of genes enriched in proliferation and cell cycle control similar to the