Proteins in a Leukemia-Causing Complex Act Independently and Collectively
The complicated process of creating red blood cells requires several proteins residing within a single complex to establish a network of genes. When certain proteins in the complex are dysregulated, leukemia can occur.
The proteins GATA-1 and Scl/TAL1 (Stem Cell Leukemia/T-cell Acute Lymphocytic Leukemia-1) are the master regulators driving the normal process, but at least three other proteins with poorly defined roles reside within the complex - LMO2, ETO-2, and LDB1.
Some of the proteins bind to portions of genes, while others communicate with other proteins that act on genes, but it's been thought that they all work in an intertwined way to complete the critical steps involved in producing red blood cells.
Now researchers in the laboratory of Dr. Emery Bresnick of the Department of Cell and Regenerative Biology in the University of Wisconsin School of Medicine and Public Health and the UW Carbone Cancer Center have found that two of the proteins, ETO-2 and LMO2, act independently in addition to collectively to achieve the complex's common end.
The finding that two components of the multi-protein complex exert very different functions was entirely unexpected.
The discovery, reported recently in Proceedings of the National Academy of Sciences, has implications not only for understanding how the complexes work but also how different cancers can arise when different proteins are dysregulated.
"We know that perturbations in the proteins in this complex can lead to different kinds of leukemias," says Bresnick, an expert on mechanisms underlying hematopoiesis, gene expression and GATA protein function.
Disrupted GATA-1, for example, is linked to megakaryoblastic leukemia, disrupted ETO-2 is linked to acute myeloid leukemia, disrupted E2A is associated with acute pre-B-cell lymphocytic leukemia and disrupted SclTAL-1 is associated with acute T-cell leukemia. Disrupted LMO2 is also associated with acute T-cell leukemia.
The researchers focused on understanding the normal function of ETO-2 and LMO2, knocking down these proteins with RNA interference to establish their contributions to the overall gene expression profile of the cell.
"We demonstrated that these two proteins perform very different functions, even though it was assumed that they would contribute to a common function of the complex," says Bresnick.
Knocking down ETO2 and LMO2 differentially affected the activity of genes related to the regulation of blood precursor cells.
"In addition, the overall flavor of the genes regulated by ETO2 versus LMO2 -that is, their characteristics in terms of their biology-differed significantly," Bresnick says.
Components with different functions diversify the nature of a complex, and awareness of this diversity may help scientists as they study the numerous other complexes known to exist.
The fact that individual components within the complex affect genes differently may explain why different proteins can contribute on their own to different malignancies, says Bresnick.
"Considerably more work needs to be conducted to discover key mechanisms underlying these malignancies," he says. "Such mechanisms could yield 'druggable' targets for the development of novel therapeutics for human leukemias."
Date Published: 03/22/2011