title: T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients.
abstract: Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell survival and proliferation preferentially in U-CLL cases, whereas the PI3K/Akt inhibitor LY294002 blocked HB57-dex induced telomerase activation. Although both U-CLL and M-CLL clones exhibited similar membrane proximal signaling responses to HB57-dex, telomerase activity and cell proliferation, when inducible in M-CLL, differed. B-CLL cells stimulated using bivalent F(ab')(2) -goat anti-μ antibody (goat anti-μ) exhibited higher membrane proximal response in U-CLL than M-CLL cells, whereas telomerase activity, cell survival, and proliferation were induced to lower levels than those induced by HB57-dex. In normal B lymphocytes, HB57-dex induced less protein phosphorylation but more cell proliferation and survival than goat anti-μ. Although both anti-BCR stimuli induced comparable telomerase activity, normal CD5(+) B cells preferentially exhibited higher hTERT positivity than their CD5(-) counterparts. These findings provide an understanding of how BCR-mediated signals impact telomerase modulation in IGHV mutation-based subgroups of B-CLL and normal B cells.
authors.affiliation: Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA. rdamle@nshs.edu
authors.forename: Rajendra N
authors.initials: RN
authors.lastname: Damle
authors.forename: Sonal
authors.initials: S
authors.lastname: Temburni
authors.forename: Taraneh
authors.initials: T
authors.lastname: Banapour
authors.forename: Santanu
authors.initials: S
authors.lastname: Paul
authors.forename: Patricia K A
authors.initials: PK
authors.lastname: Mongini
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000328:Adult; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019098:Telomerase / Q000378:metabolism*
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase