Biclonal Low-Grade B Cell Lymphoma as Detected by Multiparametric Flow Cytometry in Blood and Marrow.

Biclonal B cell lymphomas (BCL) of two different low-grade components are rare. Multiparametric flow cytometry (MFC) is an integral tool in lymphoma diagnosis and very efficient in picking up BCL cases, especially when the associated second component is small. We studied the incidence of BCL in the routine blood and marrow samples sent for immunophenotyping by MFC. A total of 376 cases were analyzed retrospectively. We studied their clinical, immunophenotypic, molecular, and cytogenetic findings with literature review. We found five cases of BCL with two different clonal low-grade B cell components at an incidence of 1.3%. All cases were males with a median age of 68 years. The chronic lymphocytic leukemia (CLL) clone was present in all 5 cases. The other associated component in cases 1 to 5 were lymphoplasmacytic lymphoma, follicular lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, and monoclonal B cell population of non-CLL type respectively. Diagnosing BCL may be challenging and may also go undiagnosed when the second component is petite and overshadowed by the more significant component. It may be critical if the small, unnoticed lymphoma component is of a more aggressive type. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01625-y.

Aminopeptidase inhibition as a targeted treatment strategy in myeloma.

Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics. It causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but is able to overcome the microenvironmental protective effects, inhibiting the proliferation of myeloma cells bound to BMSCs and the increase in vascular endothelial growth factor levels seen when myeloma cells and BMSCs are bound together. Additive and synergistic effects are seen with bortezomib, melphalan, and dexamethasone. Apoptosis occurs via both caspase-dependent and non-caspase-dependent pathways with an increase in Noxa, cleavage of Mcl-1, and activation of the unfolded protein response. Autophagy is also seen. CHR-2797 causes an up-regulation of genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases, and amino acid deprivation response genes. In conclusion, inhibiting protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell apoptosis and represents a novel therapeutic approach that warrants further investigation in the clinical setting.