A type of chronic blood cancer called myeloproliferative neoplasms (MPN) can often be present in patients in a relatively benign state for years. Some patients require treatment, while others can undergo a period watchful waiting without treatment. However, in a small subset of these patients, this slower paced disease can transform into a very aggressive cancer called secondary acute myeloid leukemia (sAML). Little is known about this transformation, and there are few effective treatment options for patients who develop this more aggressive form of blood cancer.
But new research published in the journal Nature Cancer by investigators at Washington University School of Medicine have discovered an important transition point in the change from chronic to aggressive cancer. Further, they have shown that blocking a key molecule in the transition pathway in mouse models of the disease prevented this transition, a finding that could suggest new treatments for this form of leukemia.
“Secondary acute myeloid leukemia has a grim prognosis,” said senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at the School of Medicine. “Almost every patient who develops acute leukemia after a history of myeloproliferative neoplasms will die from the disease. Therefore, a major focus of our research is to better understand this conversion from chronic to aggressive disease and to develop better therapies and, hopefully, prevention strategies for these patients.”
According to the new research, the key inhibiting molecule called DUSP6, plays an important role in overcoming the resistance sAML often develops in response to treatment with drugs called JAK2 inhibitors. These drugs are anti-inflammatory inhibitors that are also used to treat rheumatoid arthritis.
“These patients are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy, so we’re also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition,” noted Oh.
The researchers performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells in order to identify aberrantly increased expression of DUSP6 both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors. DUSP6 stood out as highly expressed in the 40 patients whose tumors were analyzed.
To examine potential treatment for sAML the investigators deleted the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer. The researchers also tested a drug compound that inhibits DUSP6 and found that the compound, which is only available for animal research, stopped progression of the chronic disease to the aggressive disease in two different mouse models of the cancer and in mice with human tumors sampled from patients. Reducing DUSP6 levels both genetically and with a drug also reduced inflammation in these models.
Since the drug that inhibits DUSP6 is not available for human clinical trials, Oh and his colleagues are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6 and that they showed is also required to perpetuate the negative effects of DUSP6. There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1. Oh’s team is interested in investigating these drugs for their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition.
“A future clinical trial might enroll myeloproliferative neoplasm patients who are taking JAK2 inhibitors and, despite that, show evidence of their disease worsening,” Oh said. “At that point, we might add the type of RSK inhibitor that’s now in trials to their therapy to see if that helps block progression of the disease into an aggressive secondary acute myeloid leukemia. A newly developed RKS inhibitor is in phase 1 clinical trials for patients with breast cancer, so we’re hopeful our work provides a promising foundation for developing a new treatment strategy for patients with this chronic blood cancer.”