The cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclin-dependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy. Abbreviations: aa, amino acid; AR, androgen receptor; ATM, ataxia telangectasia mutant; ATR, ATM and Rad3-related; CDK, cyclin-dependent kinase; ChREBP, carbohydrate response element binding protein; CIP, CDK-interacting protein; CHK1/2, checkpoint kinase 1/2; CKI, CDK inhibitor; DDR, DNA damage response; DMP1, cyclin D-binding myb-like protein; DSB, double-strand DNA break; DNA-PK, DNA-dependent protein kinase; ER, estrogen receptor; FASN, fatty acid synthase; GSK3β, glycogen synthase-3β; HAT, histone acetyltransferase; HDAC, histone deacetylase; HK2, hexokinase 2; HNF4α, and hepatocyte nuclear factor 4α; HR, homologous recombination; IR, ionizing radiation; KIP, kinase inhibitory protein; MCL, mantle cell lymphoma; NHEJ, non-homologous end-joining; PCAF, p300/CREB binding-associated protein; PGC1α, PPARγ co-activator 1α; PEST, proline-glutamic acid-serine-threonine, PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; RB1, retinoblastoma protein; ROS, reactive oxygen species; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; UPS, ubiquitin-proteasome system; USP22, ubiquitin-specific peptidase 22; XPO1 (or CRM1) exportin 1.

The molecular mechanisms underlying cancer resistance remain elusive. One possible explanation is that cancer stem cells (CSCs) elude drug treatment, emerge and reproduce a tumor. Using multiple myeloma as a paradigm, we showed that cancer stem-like cells (CSLCs) appear after genotoxic stress because of their intrinsic properties. However, these properties do not drive the emergence of the CSLCs. Following genotoxic stress, remaining DNA damages lead to a senescence-associated secretory phenotype (SASP). Senescent cells, which are the non-CSLCs, secrete chemokines contributing to the emergence, maintenance and migration of CSLCs. Downregulation of checkpoint protein 2, a key player of SASP, significantly reduced the emergence of CSLCs. Our results unravel a novel molecular mechanism by which SASP might promote malignancy, underlining the dual role of senescence in tumorigenesis. This mechanism, based on mutual cooperation among tumor cells, illustrates how cancer may relapse; its targeting could represent new therapeutic opportunities.

Primary mediastinal B‐cell lymphoma (PMBL) is an entity of B‐cell lymphoma distinct from the other molecular subtypes of diffuse large B‐cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin‐β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray‐zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT‐185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP‐defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild‐type cases. KPT‐185 induced a dose‐dependent decrease in cell proliferation and increased cell‐death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT‐330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild‐type protein. Am. J. Hematol. 91:923–930, 2016.

Many recent publications highlight the large role of the pivotal eukaryotic nuclear export protein exportin-1 (XPO1) in the oncogenesis of several malignancies, and there is emerging evidence that XPO1 inhibition is a key target against cancer. The clinical validation of the pharmacological inhibition of XPO1 was recently achieved with the development of the selective inhibitor of nuclear export compounds, displaying an interesting anti-tumor activity in patients with massive pre-treated hematological malignancies. Recent reports have shown molecular alterations in the gene encoding XPO1 and showed a mutation hotspot (E571K) in the following two hematological malignancies with similar phenotypes and natural histories: primary mediastinal diffuse large B cell lymphoma and classical Hodgkin’s lymphoma. Emerging evidence suggests that the mutant XPO1 E571K plays a role in carcinogenesis, and this variant is quantifiable in tumor and plasma cell-free DNA of patients using highly sensitive molecular biology techniques, such as digital PCR and next-generation sequencing. Therefore, it was proposed that the XPO1 E571K variant may serve as a minimal residual disease tool in this setting. To clarify and summarize the recent findings on the role of XPO1 in B cell hematological malignancies, we conducted a literature search to present the major publications establishing the landscape of XPO1 molecular alterations, their impact on the XPO1 protein, their interest as biomarkers, and investigations into the development of new XPO1-targeted therapies in B cell hematological malignancies.