Submitted July 17, 2007
Accepted September 13, 2007
High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia
Marco Herling, Kaushali A Patel, Michael A Teitell, Marina Konopleva, Farhad Ravandi, Ryuji Kobayashi, and Dan Jones*
Department of Medicine I, Cologne University, Cologne, Germany
Department of Hematopathology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
Stem Cell Transplantation & Cellular Therapy, University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States
Department of Leukemia, University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States
Department of Molecular Pathology, University of Texas, M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: dajones{at}mdanderson.org.
The T-cell leukemia 1 (TCL1) oncoprotein is overexpressed by chromosomal rearrangement in the majority of cases of T-cell prolymphocytic leukemia (T-PLL). In vitro, TCL1 can modulate the activity of the serine-threonine kinase AKT, a downstream effector of T-cell receptor (TCR) signaling. In a series of 86 T-PLL tumors, we show that expression of TCR, and levels of TCL1 and activated AKT are adverse prognostic markers. High-level TCL1 in TCR-expressing T-PLL is associated with higher presenting white blood cell counts, faster tumor cell doubling and enhanced in vitro growth response to TCR engagement. In primary tumors and TCL1-transfected T-cell lines, TCR engagement leads to rapid recruitment of TCL1 and AKT to transient membrane activation complexes that include TCR-associated tyrosine kinases, including LCK. Pharmacologic inhibition of AKT activation alters the localization, stability and levels of these transient TCL1-AKT complexes and reduces tumor cell growth. Experimental introduction and knockdown of TCL1 influence the kinetics and strength of TCR-mediated AKT activation. We propose that in T-PLL, TCL1 represents a highly regulated, targetable modulator of TCR-mediated AKT growth signaling.
