JAX researchers find accurate, reliable manner to identify the origin of leukemia cells -
Each cancer starts with a single cell, and Jackson Laboratory (JAX), researchers found an accurate and reliable way - whole genome profiling of open chromatin -. to identify the type of cells that leads to a particular case of leukemia, a precious key for cancer prognosis and outcome
"Knowing the original cell of the cancer cells may provide insight into sub -types tumors and possibly diagnostic and therapeutic benefit, "says Assistant Professor Jennifer JAX Trowbridge, Ph.D., lead author of the study published July 11 in Nature Communications ." However, the methods existing to identify the original cells from samples of tumor cells in bulk have been unsuccessful. "
chromatin is the material in the cell nucleus which condenses to form chromosomes during division cell and is composed of DNA, proteins called histone and RNA. Each type of cell has a characteristic chromatin structure which includes closed chromatin which is tightly wound around nucleosomes and is relatively inactive, and chromatin open stretches of looser material that interact with regulatory elements encoded in DNA.
Trowbridge hypothesized that chromatin analysis open in tumor cells in bulk could provide an improved method can identify the original cancer cells due to cell type specificity of the structure chromatin.
The laboratory worked with a mouse model of acute myeloid leukemia (AML) driven by expressing MLL-AF9, a fusion oncogene formed by a chromosomal translocation between human chromosomes 9 and 11. they started with normal cellular five distinct types found in the bone marrow in mice and humans: hematopoietic stem cells in long-term (CSH), short-term HSCs, multipotent progenitor cells, common myeloid progenitor cells and granulocyte-macrophage progenitors. AML that has developed from these original cells had different penetrance and aggressiveness when grafted in mice, with branch lines of stem cells are progenitor lines under the most aggressive and engaged. These models were also reflected in the frequency of leukemia-initiating cells in each cell line with the CSH with the highest frequency and committed progenitors with the lowest.
the profile of open chromatin in these samples separate AML, and compare them to open models of chromatin in normal cells, Trowbridge worked with Duygu Ucar, Ph.D., assistant professor JAX which develops computer models to study gene regulation including chromatin structure. Together, they identified the signatures open chromatin and gene expression profiles in AML samples that may allow AML derived stem cells to be distinguished from the original progenitor cells AML.
These results support the human data indications that the step of progenitor cells when it turns into leukemia has an impact on its clinical progression, with the cell earlier stage cancers being more original aggressive.
The researchers note that, with further study of open chromatin in normal human stem and progenitor cell types and AML patient cohorts, this profiling approach will identify specific areas with a prognostic significance based on the original cell; in other words, a useful biomarker of human cancer
Moreover, Trowbridge said, collaboration between his laboratory and UCAR -. between wet bench and scientific computing with complementary strengths in modeling the mouse and human genome - is a very promising model for future discovery.
"This study would not have been possible without close cooperation with our colleagues calculation that have great expertise in human genomics. This study took advantage of genomic sequencing technologies and advanced genome that were new to us, and allowed us to quickly extract the maximum value from these technologies, integrate and compare our results with human genomic data, and reveal the biological mechanisms underlying new relevance with the most promising translation that we will continue to study. "
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