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Life Finds a Way

December 4, 2020

Dr. Abdel-Wahab presents his talk, Understanding and
Targeting Spliceosomal Gene Mutations in Leukemia.

In the beginning, there was chaos. Inorganic compounds swirled in and out of phase, light and dark, mixed in a haze of lifeless yet limitless potential; physics and chemistry unrepentantly contemplated the depths of their power with no regard for their as yet reclusive cousin, biology. Then, after millennia of failure after failure to progress beyond the lifeless miasma of the early Earth, there came a flicker. A chance collision occurred between carbon, nitrogen, and hydrogen, between thermal, electric, and kinetic energy, between the raw lust for entropy and the ephemeral lure of order, all coalescing into something new, something simple, something to change the universe: RNA. So says the theory of the “RNA World.” Out of nothing, something. Out of chaos, order. Out of improbability, life in its simplest form. RNA had the capability to store information, to enzymatically drive interactions between proteins, and ultimately, to transcend the impermanence of the RNA world by morphing into the stable DNA that is our ancestor.

In this way, RNA is perhaps the most historically significant molecule in our bodies, but it is only now, after billions of years, that we have the capacity to look beyond its basest functions and recognize its existential importance in driving life forward beyond the status quo. When extinction is at hand, when apoptosis is on the horizon, when there is only the void, life finds a way. This is true for Earth, for humans, and for our own cells, even when we may prefer that they die. What is a leukemia cell but a cell that has given in to the most fundamental instinct of its genetic code? To exist. To live on. To persist. And given that, why in our effort to contain a cell’s uncontrolled need to exist would we not turn to the molecule with the greatest history of forcing life into being? Not DNA, targeted by so many of our chemotherapy agents, but RNA. Perhaps the reason we have had such middling success in interrupting the expansion of acute myeloid leukemia (AML) cells is that we have been targeting the wrong replication machinery. It is time to expand our focus beyond the genome, to the epigenome, the transcriptome, and the spliceosome. View the pre-recorded Scientific Program session “RNA in Normal and Malignant Hematopoiesis,” then tune in on Saturday, December 5, at 12:00 noon Pacific time, for the live Q&A with the speakers to learn the enormous potential of this new frontier in cancer and hematology research.

Dr. Christopher Burge, who recently published the groundbreaking findings of the ENCODE project aimed at mapping the functions of RNA in genomic expression via the identification of RNA binding protein (RBP) sites, opens the session by discussing the varying ways that RNA processing and post-translational activities can affect protein expression. Alternative splicing and other modifications of primary transcripts can significantly affect the translation of the genetic code into functional proteins. While this process is just now being recognized, one can imagine, as is often the case, that understanding the mechanisms behind how we get from A to Z within the cell could have massive therapeutic implications down the line.

Dr. Omar Abdel-Wahab dives further into the interplay between the genome, transcriptome, spliceosome, and proteome and its contribution to hematologic malignancy. He notes that mutations in splicing machinery are very common in AML and myelodysplastic syndromes, with a frequency that increases with age. This discovery has the potential to be especially important for the treatment of these diseases, since modern treatments such as chimeric antigen receptor T-cell therapy and targeted immune therapies that are so promising for acute lymphoblastic leukemia and other malignancies, are useful only for cancer cells that express identifiable surface antigens. At least currently, these targets do not exist for AML, but a splicing mutation that could differentiate those cancerous cells from normal cells could represent another potential therapeutic target, as these cells are especially sensitive to further perturbations in splicing function. Drugs targeting cells with abnormal splicing function are already being tested in clinical trials, have been approved by the U.S. Food and Drug Administration, and are used for noncancer monogenic diseases such as muscular dystrophy and spinal muscular atrophy. Though the mutation profile is more complex for a disease like AML, the prevalence of splicing mutations within this population provides hope that the ability to target them may represent a turning point in the fight against AML.

Dr. Kristin Hope covers the topic of RBPs in this session with a greater focus on therapeutics and just how close we may be to finding the Achille’s heal of leukemic stem cells that has for so long eluded us. Using an in vivo screening process, her lab has identified a list of RBPs that they feel highly confident are regulators of clonal expansion and essential for leukemic cell function. They dove deep into the mechanisms through which those factors function and their targets are modified, and have had very promising results in inhibiting leukemic cell activity by targeting those RBPs — a result that may represent the capturing of an entirely new therapeutic class aimed at drugging the epigenome.

We evolved beyond the RNA world long ago, but the echoes of its influence live on at the most basic levels of our cellular biology and, it turns out, at the basic levels of cancer biology. Perhaps it is thus only by returning to the world of RNA that we can find the therapeutic solutions that have remained just out of reach. Tune in to this session chaired by Dr. Kathrin Bernt to dive back into the chaos, where you will find that RNA may hold the key to establishing order once again.

Dr. Glaros indicated no relevant conflicts of interest.

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