Mantle cell lymphoma and the evidence of an immature lymphoid component.

Mantle cell lymphoma (MCL) is a rare B cell malignancy. The classical MCL subtype is positive for translocation t(11;14), SOX11 expression, and characterized as a mature B cell neoplasm. While it is evident that differentiated B lymphocytes comprise the principal constituent of this malignancy, the possibility of an immature component involving immature progenitor, precursor, or even multipotent stem cells exists. It is now known that many hematologic malignancies are preceded by clonal hematopoiesis or a premalignant phase, which may involve early progenitors, and that such mutations can persist following treatment. Here, we thematically review and discuss the existing evidence pointing to an immature contribution of MCL in some cases. With the ongoing transition towards comprehensive genomic profiling, it is now possible to thoroughly investigate whether an immature genomic profile accompanies the morphologically lymphoblastic appearance of the blastoid subtype. This profile may include the expression of genes related to the pre-B cell receptor or genes required for the development and differentiation of B cell progenitors and precursors, such as transcription factor, SOX4, and the terminal transferase, DNTT. Research into the likely immature component of MCL is motivated by the relevance in treatment strategies because such cells potentially constitute a reservoir with increased resistance. In conclusion, further evidence on the concept, and definition, of lymphoma progenitors, precursors, or stem cell involvement in MCL is highly warranted.

Molecular characterization of sorted malignant B cells from patients clinically identified with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a tumor with a poor prognosis. A few studies have examined the molecular landscape by next-generation sequencing and provided valuable insights into recurrent lesions driving this heterogeneous cancer. However, none has attempted to cross-link the individual genomic and transcriptomic profiles in sorted MCL cells to perform individual molecular characterizations of the lymphomas. Such approaches are relevant as MCL is heterogenous by nature, and thorough molecular diagnostics may potentially benefit the patient with more focused treatment options. In the work described here, we used sorted lymphoma cells from four patients at diagnosis and relapse by intersecting the coding DNA and mRNA. Even though only a few patients were included, this method enabled us to pinpoint a specific set of expressed somatic mutations, to present an overall expression profile different from the normal B cell counterparts, and to track molecular aberrations from diagnosis to relapse. Changes in single-nucleotide coding variants, subtle clonal changes in large-copy-number alterations, subclonal involvement, and changes in expression levels in the clinical course provided detailed information on each of the individual malignancies. In addition to mutations in known genes (e.g., TP53, CCND1, NOTCH1, ATM), we identified others, not linked to MCL, such as a nonsense mutation in SPEN and an MYD88 missense mutation in one patient, which along with copy number alterations exhibited a molecular resemblance to splenic marginal zone lymphoma. The detailed exonic and transcriptomic portraits of the individual MCL patients obtained by the methodology presented here could help in diagnostics, surveillance, and potentially more precise usage of therapeutic drugs by efficient screening of biomarkers.

Human DREF/ZBED1 is a nuclear protein widely expressed in multiple cell types derived from all three primary germ layers.

Drosophila DNA replication-related element binding factor (DREF) is a transcription regulatory factor that binds the promoters of many genes involved in replication and cell proliferation and is required for normal cell cycle progression. Human DREF/zinc finger BED domain-containing protein 1 (ZBED1), an orthologue of Drosophila DREF, also has DNA binding activity, but its cellular functions remain largely uncharacterized. Herein, we show that ZBED1 is a chromatin-associated nuclear protein with a wide expression profile in human tissues from all three primary germ layers. For instance, ZBED1 was expressed in mesodermal-derived epithelial cells of the reproductive system and urinary tract, in endodermal-derived epithelial cells throughout the gastrointestinal tract, and in epidermal epithelium from the ectoderm. ZBED1 was also expressed in connective tissue and smooth muscle cells of multiple organs. To investigate whether ZBED1 is implicated in cell proliferation, similar to Drosophila DREF, we compared the tissue distribution of ZBED1 to that of the proliferation marker Ki-67. ZBED1 and Ki-67 were co-expressed in many epithelial tissues, but ZBED1 expression extended widely beyond that of Ki-67-positive cells. In other tissues, ZBED1 expression was more restricted than Ki-67 expression. These results suggest that ZBED1 is not a cell proliferation-associated factor such as Drosophila DREF, and our study adds to the cumulative understanding of the functions of ZBED1 in human cells and tissues.