High TCL1 levels are a marker of B-cell receptor pathway responsiveness and adverse outcome in chronic lymphocytic leukemia

Stromal cells modulate TCL1 expression, interacting AP-1 components and TCL1-targeting micro-RNAs in chronic lymphocytic leukemia

“…18,19 Experimental deregulation of human (transgenic) TCL1 in murine B cells causes B-cell proliferations resembling aggressive human CLL, 25 demonstrating that TCL1 overexpression is a causal event in the development of CLL. The event(s) responsible for deregulation of TCL1 in human CLL are, in the absence of detectable chromosomal aberrations involving its locus, 20 largely unknown.…”

“…For immunoblot assays in 11 CLL according to published protocols, 19 we used the following primary antibodies: anti-phospho(p)AKT (Ser473) clone D9E (Cell Signaling Technology/New England Biolabs, Frankfurt, Germany), anti-MCL1, anti-GAPDH, anti-JUND, anti-FOSB, anti-Akt1/2 (all Santa Cruz Biotechnology, Heidelberg, Germany), anti-TCL1 18 as well as c-FOS (Cell Signaling Technology) and anti-b-Actin (Sigma-Aldrich). IP analysis of interacting proteins in primary CLL cells (seven cases) was performed as described previously.…”

“…19 Protein lysates were immunoprecipitated either with mouse IgG isotype antibody (Sigma-Aldrich) or mouse anti-TCL1 antibody (clone 1 --21). 18,19 Isolated protein complexes were separated by denaturing SDS-PAGE, and TCL1-interacting partners were detected by subsequent western blots using the following antibodies (same sources as above): rabbit anti-JUND, goat anti-FOSB, rabbit c-FOS and rabbit anti-AKT1/2. Incubations of PAGE-separated IP's with TCL1 as well as of the pre-IP lysates (input) with mouse anti-b-Actin served as controls.…”

“…18 Upon BCR engagement, TCL1 and AKT co-recruit to BCR membrane-activation complexes, with TCL1 expression levels predicting BCR signaling and growth responses. 19 However, chromosomal aberrations that constitutively activate TCL1, as seen in T-cell prolymphocytic leukemia, have not been identified in CLL, 20 and the mechanism(s) regulating TCL1 expression in CLL remain largely unknown except for reports on posttranscriptional TCL1 regulation by micro (mi)-RNAs. 21 The association of higher TCL1 levels in those CLL with the del(11q23) aberration 19 recently has been explained by concurrent losses of miRNA-34b/miRNA-34c.…”

“…19 However, chromosomal aberrations that constitutively activate TCL1, as seen in T-cell prolymphocytic leukemia, have not been identified in CLL, 20 and the mechanism(s) regulating TCL1 expression in CLL remain largely unknown except for reports on posttranscriptional TCL1 regulation by micro (mi)-RNAs. 21 The association of higher TCL1 levels in those CLL with the del(11q23) aberration 19 recently has been explained by concurrent losses of miRNA-34b/miRNA-34c. 22 In the presented study, we detected a robust increase in the expression of TCL1 along with decreases of the FOS/JUN AP-1 family members as one of the most significant and consistent molecular events after CLL-BMSC co-culture.…”