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). 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.

• Authors: Marco Herling, Kaushali A Patel, Michael A Teitell, Marina Konopleva, Farhad Ravandi, Ryuji Kobayashi, Dan Jones
• Journal: Blood (Blood) Vol. 111 Issue 1 Pg. 328-37 (Jan 01 2008) ISSN: 0006-4971 [Print] United States
• PMID: 17890451 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins
• Receptors, Antigen, T-Cell
• TCL1A protein, human
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Cell Division (physiology)
• Gene Expression Regulation, Leukemic
• Humans
• Immunophenotyping
• Leukemia, Prolymphocytic (genetics, metabolism, pathology)
• Leukemia, T-Cell (genetics, metabolism, pathology)
• Phosphorylation
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Antigen, T-Cell (metabolism)
• Signal Transduction (immunology)
• T-Lymphocytes (pathology, physiology)