High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia.
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.
Herling
Marco
M
Department of Hematopathology, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Patel
Kaushali A
KA
Teitell
Michael A
MA
Konopleva
Marina
M
Ravandi
Farhad
F
Kobayashi
Ryuji
R
Jones
Dan
D
D002455:Cell Division / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016130:Immunophenotyping; D015463:Leukemia, Prolymphocytic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology
D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C090851:TCL1A protein, human; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt