Abstract
Non-Hodgkin’s lymphoma (NHL) is the most common hematological malignancy in the US. Many types remain incurable despite response to initial therapy and achievement of complete remission (CR). Advanced laboratory techniques like multicolor flow cytometry (FCM) and polymerase chain reaction (PCR) have demonstrated persistence of rare malignant cell population post therapy. However, the functional and biological characteristics of this population have not been elucidated.Established B-lymphoma cell lines (B-NHL) and patient-derived samples (PDS) were analyzed using 8-color FCM. CD34+ sub-population was enriched using in vitro exposure to 2-chlorodeoxyadenosine (2-CdA) and by CD34 magnetic beads. Genetic analysis of cell fractions was done by karyotyping and array comparative genomic hybridization (aCGH). Sensitivity to chemotherapy was assayed by short-term in vitro exposure to chemotherapy. Clonogenicity was determined by soft agar colony formation assay, and proliferation was determined using DNA staining with propidium iodide and FCM.FCM demonstrated the presence of a minute sub-clone of monotypic B-cells that express CD34 in B-NHL cell lines (3 of 3) and in PDS (8 of 8). This sub-population enriched up to 50 fold in vitro by exposure to 2-CdA and up to 80% purity by CD34 magnetic bead column isolation. Except for CD34 expression, this population expressed identical phenotype and genotype to parent cells, but was more proliferative, Hoechst 33342-positive, clonogenic, and resistant to chemotherapy compared with the CD34- population.The isolated CD34+ monotypic B-cells may contribute to resistance of certain NHL to treatment and should be targeted by potential new drugs for NHL.
Highlights
Non-Hodgkin’s lymphoma (NHL) is the 7th most common cancer in the United States
Enrichment was highest in the follicular lymphoma cell line, Wayne State University (WSU)-follicular small cleaved cell lymphoma (FSCCL) reaching more than 50 folds at 72 hours compared with control (13.2% vs 0.26%, Table 1), followed by WSU-Waldenström’s macroglobulinemia (WM), 10 fold, (2.36% vs 0.23%) and least in the aggressive diffuse large B-cell lymphoma cell line, WSU-DLCL2 (1.25% vs 0.71%)
CD34 is considered a marker of normal hematopoietic stem cells and for some acute myeloid leukemia, its expression is not limited to such cells
Summary
Non-Hodgkin’s lymphoma (NHL) is the 7th most common cancer in the United States. NHL is comprised of a growing list of more than 100 entities based on pathologic, clinical and genetic features [2]. The natural history of NHL is quite variable with some types being slow growing ‘indolent’ (~40%) while others are aggressive or very aggressive [3, 4]. The slow growing NHLs remain incurable whereas the aggressive types are curable 20–40% of those will relapse and may become incurable [5]. All types of NHL are usually responsive to initial treatment and often achieve complete remission (CR), which is a prerequisite to cure. Despite achievement of CR, all indolent NHLs and some aggressive ones relapse
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