Researchers have identified a new mathod to defeating Chronic Myelogenous Leukemia, which tends to affect older adults, even within the face of resistance to existing drugs.
The new findings were published on September 17th in Nature Communications.
Almost all patients with chronic myelogenous leukemia, or CML, have a faulty, cancer-causing gene, or “oncogene” called BCR-ABL1. BCR-ABL1 turns a daily somatic cell (a unique sort of cell which will become other sorts of cells then reproduce those cells during lifetime) within the bone marrow into a CML somatic cell that produces malformed blood cells. And rather than the CML somatic cell dying when it should be scheduled to try to so, the oncogene causes it to stay producing even more of those faulty blood cells.
Advances in treatment since the turn of the millennium are extremely successful at combatting the disease in patients with this oncogene. Drugs called Tyrosine Kinase Inhibitor (TKI) have completely transformed the prognosis of individuals with such leukemias and with fewer of the side effects of other cancer treatments. In most cases, cancer goes into remission and patients live for several years following diagnosis.
BCR-ABL1 directs the assembly of an abnormal sort of tyrosine kinase, an enzyme that ‘turns on’ many sorts of proteins through a cascade of chemical reactions referred to as signal transduction–in effect communication via chemistry.
Miscommunication resulting from the faulty enzyme is what promotes the expansion of the leukemic cells. By stopping this communication within CML stem cells, TKI signal transduction therapy inhibits their growth and brings a halt to their production of the malformed blood cells.
However, TKIs only control the disease; they do not cure it. Drug resistance can develop during a patient because while TKIs work well on proliferative mature CML cells that are actively reproducing, they’re less effective at inducing necrobiosis on the part of CML stem cells that are quiescent.
Quiescence is an “idling” stage within the life cycle of a cell during which it basically just rests and hangs out for extended periods of your time in anticipation of reactivation, neither replicating nor dying.
“If CML stem cells are during a quiescent phase, they’re otherwise left untouched by TKI treatment, then survive to potentially cause a relapse,” said Kazuhito Naka, paper author and a professor from the Department of somatic cell Biology of Hiroshima University’s Research Institute for Radiation Biology and Medicine.
But the researchers found in mouse models that if they disrupt Gdpd3–a different, non-oncogene gene–then the self-renewal capacity of the CML stem cells is sharply decreased.
Gdpd3 directs the assembly of an enzyme for a specific sort of lipid that appears to play a key role in regulating the quiescence of CML stem cells in an oncogene-independent fashion.
In other words, the Gdpd3 gene involved within the production of this lipid is essentially liable for the upkeep of CML stem cells. The researchers had broken their quiescence.
Crucially, when the researchers disrupted the Gdpd3 gene encoding these lipids, leukemia relapse within the mice was significantly reduced, even when the BCR-ABL1 oncogene wasn’t disrupted.
“This potentially provides another path to arresting these leukemias–and maybe other cancers too,” said Dr. Naka, “beyond having to wrestle with the BCR-ABL1 oncogene.”
While the researchers have discovered a replacement, biologically significant role for this particular lipid in causing the recurrence of CML, they still don’t fully understand the precise way this happens. The researchers now want to research the mechanisms involved and whether this lipid also plays a task within the quiescence of the cancer stem cells that cause solid tumors, not just in leukemias, and thus in these cancers’ recurrence and growth also
Hiroshima University and Newsmedical.net
Naka, K., et al. (2020) The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukemia stem cells. Nature Communications. doi.org/10.1038/s41467-020-18491-9.