In 2008 we were able to uncover such mechanism [23]. We hypothesized that some CLL samples might have gain of function mutations in TCL1, and that functional analysis of these mutations could point to molecular mechanisms of Tcl1 mediated B-cell transformation. Thus, we sequenced the TCL1 gene in 600 CLL samples and identified two heterozygous mutations resulting in amino acid substitutions, T38I and R52H. Interestingly, RT-PCR results showed that the T38I mutant TCL1 mRNA was the major expressed allele in the CLL of origin, accounting for ~80% of the TCL1 mRNA, and the R52H allele was the only allele expressed [23]. Since NF-kB activation is critical in CLL development, we first examined if TCL1 mutants show gain of function in NF-kB activation. Using reported system we showed that Tcl1 activated NF-kB activity 2–4 fold by a mechanism independent of Akt. However, in these experiments the Tcl1 mutants did not exhibit gain of function in the activation of NF-kB [23].
