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August 27, 2018

Leukemia mRNA Processing Pathways Contribute to Disease Progression

Intronic Polyadenylation Inactivates Tumor Suppressor Genes

Leukemia mRNA Processing Pathways Contribute to Disease Progression

Blood sample from a patient with chronic lymphocytic leukaemia (CLL). Red and white blood cells, scanning electron micrograph (SEM). [Science Photo Library - Steve Gschmeissner/Getty Images]

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    Christine Mayr, M.D., Ph.D., lead researchers who identified that the mechanism contributing to cancer progression was not due to mutations in the DNA.

    Certain cancers, including some leukemias, have notably low levels of genomic mutations. A new study has found that widespread truncation of mRNAs inactivates tumor suppressor genes, functionally mimicking genetic alterations seen in cancer.

    The researchers, led by Christine Mayr, M.D., Ph.D., associate member of the cancer biology and genetics program at Memorial Sloan Kettering Cancer Center (MSKCC), identified that the mechanism contributing to cancer progression was not due to mutations in the DNA, rather they originated through the process of intronic polyadenylation (IPA) resulting in truncated mRNAs. These mRNAs encode proteins that lack the tumor-suppressive functions of the corresponding full-length proteins with some acting in an oncogenic manner. This work, “Widespread intronic polyadenylation inactivates tumor suppressor genes in leukemia,” published in Nature, indicates a novel mechanism of chronic lymphocytic leukemia (CLL) development.

    Markus Müschen, M.D., Ph.D., professor & chair of the Department of Systems Biology and the associate director at the City of Hope Comprehensive Cancer Center tells GEN that “IPA is a fundamentally novel mechanism of functional inactivation of tumor suppressors.” He adds that “this seems to be particularly relevant in tumors that, like B-CLL, have a relatively low burden of somatic mutations.”

    Dr. Mayr says that this work is an offshoot from the primary interest of her lab, which is the 3’ UTR region of messenger RNA. Roughly five years ago, the team developed a method that allowed the mapping of the 3’ ends of the entire transcriptome. This project resulted in a large-scale analysis of the 3’ UTR data, during which they noticed thousands of mRNA ends (or “peaks” in the 3’-seq data) in introns. Dr. Mayr admits that she first thought that the peaks were an artifact. However, a hypothesis took hold that this mRNA heterogeneity in normal cells was a mechanism to diversify the proteome.

    During the course of this research, Dr. Mayr had an underlying idea that these changes in mRNA processing may mimic cancer mutations. With access to samples from CLL patients, her lab was able to explore this further. They found that some peaks are upregulated in cancer. Although many peaks were not located in tell-tale oncogenic genes, the inclusion of MGA, a very important gene in CLL and a known negative regulator of MYC, on the list was a key finding. The “aha moment” was when the peak was found at the same position of DNA truncating mutations. The lab verified that both mechanisms, a mutation in the DNA and a change in the RNA, make a truncated protein with a cancer promoting function. When they looked more systematically, they found an enrichment in tumor suppressor genes.

  • Global Impact of IPA on the Proteome

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    A word cloud based on the titles of all publications from the Bin Tian lab from 2003 to 2013. [The Tian Laboratory]

    Bin Tian, Ph.D., professor in the Department of Microbiology, Biochemistry and Molecular Genetics at Rutgers New Jersey Medical School, says that his lab “first reported widespread IPA occurrences of in the human genome about ten years ago, but their functions have been elusive.” He adds that Dr. Mayr’s work “shows for the first time a global impact of IPA on the proteome in cancer development.”

    Are these mRNA changes the primary cause of leukemia? Dr. Mayr is not ready to make that claim and does not exclude the possibility that DNA mutations play a role. For example, a mutation in a regulatory factor could lead to changes in mRNA processing. However, she adds that even that would not explain the massive enrichment in truncated tumor suppressor genes in leukemia samples. Her alternative hypothesis is one of selection, i.e., normal cells either make mistakes in mRNA processing or intended isoforms of proteins at a low level. However, if the truncated protein offers a survival advantage, an expansion of that clone would result.

    It remains unclear whether or not the same phenomenon is occurring in solid tumor cells. One complication is the difficulty of working within those systems. Blood cancers are a cleaner system in which to study this type of phenomenon as the immune cells can be sorted into a pure population. Therefore, every cell that is analyzed is a cancer cell. In solid tumors, there are many different cell types in addition to the tumor microenvironment, complicating the ability to work on isolated cancer cells.

    Dr. Tian is excited by the future of IPA’s role in cancer. He adds that he is eager to learn “how IPA sites are utilized to modulate the proteome under other biological contexts, such as cell differentiation, development and stress” and he “looks forward to seeing the mechanism that contributes to CLL-IPA being defined.”

    Dr. Müschen was surprised that “IPA-dependent changes of mRNA processing can apparently provide a stable oncogenic signal that drives transformation and lasts over a longer period of time.” For example, he mentions the striking result that “CARD11, a frequently mutated oncogene in B-cell tumors, can be targeted by IPA to act in an oncogenic manner.” Given that tumor cells are often addicted to oncogenic pathways (e.g., NF-kB activation by oncogenic CARD11), he would expect hardwired mechanisms to ensure constitutive activation of this pathway.”

    These mRNA events, that are not detectable at the DNA level, are widespread contributors to cancer pathogenesis. This study opens the possibility that genomic analysis is no longer sufficient for cancer diagnosis. Dr. Müschen adds that IPA may have physiological functions in regulation of gene activity and that this study “will generate substantial interest in multiple fields beyond cancer, including possible roles of IPA in normal cells.”

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