Study highlights the role of genetic “bridge” in leukemia development

A complex network of three-dimensional structures assembles to read, copy and produce the genetic materials (DNA) required for cellular function, for cells to thrive. A better knowledge of how these structures form, and the consequences when things go wrong, is a daily endeavor for scientists at Penn State College of Medicine and Penn State Cancer Institute.

Study highlights the role of genetic “bridge” in leukemia development
Four Diamonds researcher Suming Huang uses a suspension bridge to describe the genome structure that contributes to leukemia development. Image Credit: Pennsylvania State University.

A team of scientists is examining how some hard-to-treat subtypes of acute myeloid leukemia (AML) evolve as a result of changes in cellular genomic structures termed topologically associated domains (TADs) in the lab of Four Diamonds Epigenetics Program researcher Suming Huang, professor of pediatrics.

Huang is studying how the role of the human genome building block CCCTC-binding factor (CTCF) in the construction of these topological structures is affected by long noncoding ribonucleic acid (lncRNA). According to his most recent work, HOTTIP, a lncRNA, plays a vital role in the development of R-loops with DNA strands, which preserve the structural integrity required for downstream biological practices that enable leukemia to develop and advance.

Imagine a suspension bridge, The bridge itself is the TAD that allows access to the production line for a molecule called beta-catenin, which prior research has shown allows leukemia cells to develop. The bridge is assembled and supported by the towers (CTCF) and cables (HOTTIP) and the cables are anchored in place by the R-loops. Our lab demonstrated that R-loop formation is facilitated by HOTTIP.”

Suming Huang, Professor, Department of Pediatrics, Cancer Institute Researcher, Pennsylvania State University College of Medicine

The researchers concluded that after implanting AML cells into mice. AML cells that were genetically altered and unable to create R-loops in the TAD encompassing beta-catenin area were implanted in some mice, whereas AML cells that could produce R-loops in the same region were implanted in others. The mice with cells that could not create R-loops lived longer on average, indicating to the researchers that R-loops are important in leukemia development.

Without the ‘anchors’, the genetic ‘bridge’ cannot form. Understanding how genome structure contributes to leukemia development might someday allow us to identify therapeutic targets and develop next‐generation therapies.”

Suming Huang, Professor, Department of Pediatrics, Cancer Institute Researcher, Pennsylvania State University College of Medicine

Source:
Journal reference:

Luo, H., et al. (2022) HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia. Molecular Cell. doi.org/10.1016/j.molcel.2022.01.014.

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