NEW YORK, NY (Jan. 19, 2022)—To stop acute myeloid leukemia, one of the deadliest blood cancers, targeting neighboring bone cells may be a better strategy than directly targeting the cells that give rise to the disease, suggests a new Columbia study.
The new study was published Jan. 19 in Cancer Discovery, a journal of the American Association for Cancer Research.
Acute myeloid leukemia (AML) is one of the hardest-to-treat blood cancers. And though it’s possible to achieve remission with drugs that target and destroy the stem cells that give rise to leukemia, the disease usually returns with deadly consequences. Patients relapse when new types of leukemic stem cells that elude all existing treatments surface.
Trying to develop additional drugs that target new stem cells is challenging, says cancer researcher Stavroula Kousteni, PhD, because the cancer will eventually mutate to circumvent the drugs.
Her new study shows that targeting neighboring cells in the bone marrow – osteoblasts, the cells which make bone – could turn a friendly environment for leukemia cells into a hostile one.
That’s because the osteoblasts are lured into helping leukemia stem cells, Kousteni’s team, led by Marta Galán-Díez, PhD, found. The new study reveals how leukemia cells lure the osteoblasts to function to their advantage by releasing a molecule called kynurenine. Kynurenine binds to a serotonin receptor (HTR1B) on the osteoblasts, sending the message to osteoblasts to help nurture leukemic cells by secreting an acute phase response protein (SAA1). SAA1 then tells the leukemia cells to make more kynurenine, and a vicious cycle ensues that leads to more disease progression.
The crosstalk between leukemia cells and osteoblasts can be broken, Galán-Díez and Kousteni found, suggesting a way forward for new AML treatments. In experiments with mice, they found that genetically eliminating the serotonin receptor that binds kynurenine blocks the progression of leukemic cells.
And in humanized mice carrying leukemia cells from patients and experiencing an AML relapse, an experimental drug that inhibits kynurenine synthesis “had a substantial effect in combination with traditional chemotherapy, slowing disease progression,” Galán-Díez says. (The drug, called epacadostat, is being tested in other cancers).
In the same study, Kousteni and Galán-Díez observed increasing levels of kynurenine and SAA1 in AML patients and in patients with myelodysplastic syndrome (MDS), another hematological cancer that often transforms to AML. Levels of both molecules increase with MDS progression to AML and SAA1 promotes proliferation of MDS and AML cells from patients, suggesting the same partnership between MDS or leukemia cells and osteoblasts is active in the human form of disease.
“The advantage of this approach is that it doesn’t matter which stem cells are causing the disease. They all need osteoblasts to grow, and if we can stop these two types of cells from communicating, we might be able to stop the disease,” Kousteni says.
In addition, the same approach may also prevent pre-leukemic conditions like MDS from progressing.
All authors: Marta Galán-Díez (Columbia), Florence Borot (Columbia), Abdullah Mahmood Ali (Columbia), Junfei Zhao (Columbia), Eva Gil-Iturbe (Columbia), Xiaochuan Shan (University of Pennsylvania), Na Luo (Columbia), Yongfeng Liu (University of North Carolina, Chapel Hill), Xi-Ping Huang (University of North Carolina, Chapel Hill), Brygida Bisikirska (Columbia), Rossella Labella (Columbia), Irwin Kurland (Albert Einstein College of Medicine), Bryan L. Roth (University of North Carolina, Chapel Hill), Matthias Quick (Columbia), Siddhartha Mukherjee (Columbia), Raul Rabadán (Columbia), Martin Carroll (University of Pennsylvania), Azra Raza (Columbia), and Stavroula Kousteni (Columbia).
The research was funded by the NIH (grants AR054447, HL130937, P30CA013696, and P60DK020541); the Edward P. Evans Foundation for MDS Research; and a Mandl Connective Tissue Research Fellowship. The Oncology Precision Therapeutics and Imaging Core (OPTIC) at the Herbert Irving Comprehensive Cancer Center at Columbia University was used in the research.
The authors declare no potential conflicts of interest.
Instead, Kousteni has looked for treatments that make the environment around the stem cells less hospitable for any type of leukemic stem cell. “We used to think blood cancers were driven exclusively by their own genetic mutations, but in recent years we’ve begun to realize that the cancer’s surroundings play an important role,” says Kousteni, professor of physiology & cellular biophysics and director of the Edward P. Evans Center for Myelodysplastic Syndromes (MDS) at Columbia University Vagelos College of Physicians and Surgeons.
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Subversion of serotonin-receptor signaling in osteoblasts by kynurenine drives Acute Myeloid Leukemia
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