The findings reveal that disruption of immune cell differentiation is central to disease progression and provide new avenues for development of future therapeutics.
T cell acute lymphoblastic leukemia (T-ALL) accounts for 10%-15% of pediatric and 25% of adult ALL cases. A gene called TAL1/SCL is frequently activated in T-ALL patients, but exactly how it causes leukemia has not been clear.
Dr. Michelle Kelliher, from the Department of Cancer Biology at the University of Massachusetts Medical School in Worcester, Massachusetts, and colleagues examined how the TAL1/SCL protein contributes to leukemia.
The researchers demonstrate that TAL1/SCL induces leukemia by interfering with a protein called E47/HEB that regulates the expression of many different genes required for immune cell differentiation and survival.
When these genes were experimentally inhibited by TAL1/SC1 in mice, the mice exhibited abnormal immune (T cell) development, and most eventually developed leukemia.
The researchers also showed that TAL1/SCL silences gene expression by recruiting a histone deacetylase (HDAC) repressor complex, and in fact, HDAC inhibitors were very effective at inhibiting the growth of TAL1/SCL tumor cells.
"Our work demonstrates that TAL1/SCL induces leukemia by repressing E47/HEB activity, and suggests that HDAC inhibitors may prove efficacious in T-ALL patients who express TAL1/SCL. This is an important discovery, as these particular patients respond poorly to current chemotherapies and are at high risk for treatment failure," says Dr. Kelliher.
Jennifer O'Neil, Jennifer Shank, Nicole Cusson, Cornelius Murre, and Michelle Kelliher: "TAL-1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB"
Published in Cancer Cell, Volume 5, Number 6, June 2004.
Journal
Cancer Cell