Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) leukemias develop when certain chromosomal abnormalities disrupt the genes that control blood cell formation. Without the proper instructions from these genes, blood cells produced by bone marrow never fully mature; these immature cells, which can't carry vital nutrients or fight infection, then flood the body.
The researchers showed how a fusion of proteins created by flawed chromosomes can trigger leukemia development. The study also identified an enzyme's important role in this process.
The results were published online Aug. 20 and will appear in a future print issue of the journal Nature Cell Biology.
The research was led by Dr. Yi Zhang, professor of biochemistry and biophysics in the UNC School of Medicine and a Howard Hughes Medical Institute Investigator. Zhang is also a member of the UNC Lineberger Comprehensive Cancer Center. The work was supported by grants from the National Institutes of Health.
The study examined chromosomal translocation, in which a fragment of a chromosome breaks off and joins another. Chromosomes are the cellular structures that carry DNA. Translocation along chromosomes can result in the generation of fusion proteins that often "misregulate" specific genes, including genes that can cause leukemia, and is a common cause of leukemia, Zhang said. The most common chromosome translocations found in leukemia patients involve the mixed lineage leukemia gene, MLL. One of the fusion proteins that partners with MLL in leukemia is AF10.
AF10 has been shown to fuse with another protein, CALM, in patients with acute lymphoblastic leukemia or acute myeloid leukemia. But it has been unclear whether that fusion could cause leukemia, and little is known about how this CALM-AF10 fusion may lead to the disease, Zhang said. "Results from this study provide important insights into these questions," he said.
Zhang and his colleagues showed that the CALM-AF10 fusion is "necessary and sufficient" for cellular transformation to leukemia in a mouse model of the disease. They also discovered that the fusion overactivates (also called upregulation) the gene HoxA5. Moreover, upregulation of the HoxA5 gene is necessary for cellular transformation to leukemia, the study shows.
Overactive Hox genes are known to play a role in cancer, Zhang said. "In mammals, Hox genes play an important role in embryonic development. They help set the developmental pattern. They also play a role in cancer. That's why their expression must be tightly controlled."
The researchers also identified an enzyme, hDOT1L, as important for upregulating gene expression by the CALM-AF10 fusion protein.
This finding builds on earlier work by the Zhang laboratory involving another fusion protein, MLL-AF10, and the enzyme's upregulation of the Hox gene HoxA9.
Having demonstrated the role of hDOT1L in leukemia development of two different fusion proteins, the Zhang lab is exploring the possibility of developing drugs that target the hDOT1L enzyme. "Understanding the molecular mechanism underlying leukemia development will certainly help in this endeavor, Zhang said.
L.H. Lang | EurekAlert!
Gene therapy shows promise for treating Niemann-Pick disease type C1
27.10.2016 | NIH/National Human Genome Research Institute
'Neighbor maps' reveal the genome's 3-D shape
27.10.2016 | International School of Advanced Studies (SISSA)
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
27.10.2016 | Materials Sciences
27.10.2016 | Physics and Astronomy
27.10.2016 | Life Sciences