Investigators may have discovered a new way to treat mixed-lineage leukemia (MLL)-rearranged leukemia, according to research published in Cell.
The team found they could disrupt the balance between wild-type MLL proteins and MLL chimeras.
This impeded MLL leukemia cell proliferation in vitro, delayed disease progression in a mouse model of MLL-AF9 leukemia, and prolonged survival in the mice.
The investigators are now attempting to translate these findings to the clinic.
“We’ve spent the last 20 years in my laboratory trying to molecularly understand how MLL translocations cause this rare and devastating form of leukemia in children so that we can use this information to develop an effective therapy for this cancer,” said lead investigator Ali Shilatifard, PhD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois.
“Now, we’ve made a fundamentally important breakthrough.”
The investigators found that wild-type MLL protein is less stable than the MLL chimeras in MLL leukemia cells. They therefore theorized that stabilizing the wild-type copy of the protein would displace the mutated version that drives MLL-rearranged leukemia.
The team set out to identify factors regulating MLL protein degradation and found the ubiquitin-conjugating enzyme E2O (UBE2O).
The investigators said UBE2O regulates the stability of wild-type MLL in response to interleukin-1 signaling. And inhibiting interleukin-1 receptor-associated kinases (IRAKs) increases the stability and chromatin occupancy of wild-type MLL.
The team also found that IRAK inhibition displaces the MLL chimera and subunits of the super elongation complex at a subset of target genes (LGALS1, LMO2, and GNA15).
To determine the implications of these findings for treatment, the investigators tested an IRAK4 inhibitor in patient-derived cell lines, including MLL leukemia and non-MLL leukemia/lymphoma cells. The inhibitor preferentially impeded the growth of MLL-rearranged leukemia cells.
The team also tested IRAK inhibitors in a murine MLL-AF9 leukemia transplantation model. They injected the animals with IRAK inhibitors on day 19 after transplant, which is just before the mice succumb to leukemia.
The mice received injections with an IRAK1/4 inhibitor (8 mg/kg), an IRAK4 inhibitor (75 mg/kg), or vehicle control every other day for 10 days.
The investigators said both IRAK inhibitors significantly extended survival beyond the 27-day mark, when all of the vehicle-treated mice had succumbed to the disease. Two mice treated with an IRAK inhibitor (1 mouse for each drug) were still alive at day 55.
The team also treated mice with the IRAK inhibitors or vehicle control at 10 days after transplant.
Eight of the 10 mice that received the IRAK1/4 inhibitor had not developed MLL-AF9 leukemia as of day 55. And the same was true for 4 of the 9 mice that received the IRAK4 inhibitor.
However, all of the vehicle-treated mice had succumbed to the disease by the 31-day mark.
The investigators said they are now synthesizing better compounds and hope to eventually launch a phase 1 trial to test these compounds in Chicago.
