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!
Scientists enlist engineered protein to battle the MERS virus
22.05.2017 | University of Toronto
Insight into enzyme's 3-D structure could cut biofuel costs
19.05.2017 | DOE/Los Alamos National Laboratory
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.
In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...
Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...
For the first time, scientists have succeeded in studying the strength of hydrogen bonds in a single molecule using an atomic force microscope. Researchers from the University of Basel’s Swiss Nanoscience Institute network have reported the results in the journal Science Advances.
Hydrogen is the most common element in the universe and is an integral part of almost all organic compounds. Molecules and sections of macromolecules are...
22.05.2017 | Event News
17.05.2017 | Event News
16.05.2017 | Event News
22.05.2017 | Materials Sciences
22.05.2017 | Life Sciences
22.05.2017 | Physics and Astronomy