High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia

Abstract

The T-cell leukemia 1 (TCL1) oncoprotein is overexpressed by chromosomal rearrangement in the majority of cases of T-cell prolymphocytic leukemia (T-PLL).

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

“…Immunoblotting was performed on nuclear/cytoplasmic or whole-cell lysates as previously indicated, 21,30 with enhanced chemiluminescencebased detection (GE Healthcare). In selected cases, cytosol/membrane fractionation was done using modified partitioning protocols based on the manufacturer's instructions (Qproteome subfractionation kit; QIAGEN) and on specific detergent properties (NP40 or CHAPS containing buffers).…”

“…pAKT levels after stimulation were graded as "strong" (2.5-fold or higher increase of pS473-AKT), "moderate" (1.5-to Յ 2.5-fold), or "no response" (Յ 1.5-fold). TCL1 intensity was graded by immunoblot, with the B-cell line DoHH2 used as the negative control and a stably TCL1-transfected DoHH2-TCL1 subclone (method as described in Herling et al 21 ) and CD19-selected normal tonsillar B cells used as the high-and low-positive controls, respectively. TCL1 levels were graded after densitometry followed by normalization to ␤-actin levels as 0, absent (equivalent to (A) After BCR crosslinking, responsive CLL cases showed rapid ERK1/2 phospho-activation followed by variable and usually prolonged pS473-AKT induction.…”

“…[13][14][15][16][17][18][19] The T-cell leukemia 1 (TCL1) proto-oncogene, which is highly expressed in a substantial proportion of CLL, has been demonstrated to be a regulator of AKT activation in T-cell leukemias and in nonlymphocyte experimental models. [20][21][22][23] The B-cell transforming potential of TCL1 has been established in immunoglobulin heavy chain variable-region (IGHV) promoter/E-enhancer TCL1-transgenic mice that show emergence of clonal CD5 ϩ /IgM ϩ expansions resembling the course and phenotype of IGHunmutated human CLL. 24,25 We have previously described that TCL1 shows a differential and regulated expression pattern in CLL, 20 and an association of high protein levels of TCL1 with features of aggressive disease in CLL has been subsequently indicated by us and others.…”

How I treat prolymphocytic leukemia

“…In the only other large series reported from The MD Anderson Cancer Center, 5-year survival from diagnosis was 21% and poorer outcome was associated with high WBC, short lymphocyte doubling time, older age, and high expression of TCL-1 protein measured by flow cytometry and immunohistochemistry. 18 Patients will often be aware from their reading of the literature that this is an aggressive leukemia with poor OS. However, this information is largely based on retrospective data, and the outlook has improved with the introduction of newer treatment approaches.…”

Molecular characterization of neoplastic and normal “sister” lymphoblastoid B-cell lines from chronic lymphocytic leukemia

“…RT-PCR data represent β-actin normalized levels. DoHH2 B cells and their stably TCL1-transfected sublines DoHH2-TCL1 served as controls [28].…”