Biological and clinical determinants shaping heterogeneity in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an uncommon mature B-cell lymphoma that presents a clinical spectrum ranging from indolent to aggressive disease, with challenges in disease management and prognostication. MCL is characterized by significant genomic instability, affecting various cellular processes, including cell cycle regulation, cell survival, DNA damage response and telomere maintenance, NOTCH and NF-κB/ B-cell receptor pathways, and chromatin modification. Recent molecular and next-generation sequencing studies unveiled a broad genetic diversity among the 2 molecular subsets, conventional MCL (cMCL) and leukemic nonnodal MCL (nnMCL), which may partially explain their clinical heterogeneity. Some asymptomatic and genetically stable nnMCL not requiring treatment at diagnosis may eventually progress clinically. Overall, the high proliferation of tumor cells, blastoid morphology, TP53 and/or CDKN2A/B inactivation, and high genetic complexity influence treatment outcome in cases treated with standard regimens. Emerging targeted and immunotherapeutic strategies are promising for refractory or relapsed cases and a few genetic and nongenetic determinants of refractoriness have been reported. This review summarizes the recent advances in MCL biology, focusing on molecular insights, prognostic markers, and novel therapeutic approaches.

Figure 1.

Primary and secondary MCL chromosomal alterations. (A) The left panel is a schematic representation of CCND1, CCND2, and CCND3 genes and their rearrangements with IGH, IGK, and IGL genes. The size of the arrows represents their frequency. The right panel indicates the molecular subtype according to the CCND gene rearrangement and cMCL or nnMCL. Note that still there are no reported MCL cases with CCND2 or CCND3 rearrangements of the nnMCL subset. (B) Circular representation of copy number alterations (CNA) and structural variants (SV) in MCL with whole-genome sequencing (WGS) and pretreatment (45 cMCL and 16 nnMCL). In the inner side, the primary SV, t(11;14) found in all cases, was represented by a thicker black line, whereas other alterations affecting (or very near) driver genes are represented by black lines (translocations) or gray lines (insertions); in the outer side, the CNA are colored (gains in blue and losses in red). Driver genes or regions frequently targeted by SV (in addition to gains and losses) are indicated. Note that no recurrent rearrangements were found.

Figure 2.

Recurrent genomic MCL alterations identified using WGS/WES analysis. The frequencies displayed correspond to the studies detailed in Table 1. (A) Illustrates the CNA observed (overall frequency ≥2%) in 202 patients with MCL. The frequency of genomic alterations highlighted with an asterisk “∗” is based only on the Nadeu et al publication. (B) CNA identified in Nadeu et al categorized by MCL subtype. (C) Single nucleotide variants (SNVs) and insertions and deletions (indels) with overall frequency ≥2%, identified in 432 patients with MCL. (D) SNVs and indels, identified in Nadeu et al and categorized by MCL subtype. Variants with an overall frequency ≥2% in at least 1 of the MCL subtypes are displayed.