A combination of menin inhibition and KAT6A/7 inhibition significantly improved survival for NUP98-rearranged pediatric acute myeloid leukemia (AML) in AML model systems, even in menin inhibitor–resistant cells, according to findings published in Cancer Discovery.
The MYST gene family histone acetyltransferases complex proteins of KAT6A/MOZ, KAT7/HBO1, and the KAT6A/7 complex subunit BRPF1 were found to be therapeutically actionable dependencies for NUP98-rearranged pediatric AML.
“We have made a major advance in our understanding of these difficult-to-treat leukemias,” said senior co-corresponding author Charles G. Mullighan, MBBS(Hons), MSc, MD, of the Department of Pathology at St. Jude Children’s Research Hospital in Memphis, Tennessee. “We used that knowledge to provide a strong clinical rationale to try this combined approach that had striking results.”
“We found this complex is targetable with an inhibitor that interacts synergistically with menin inhibition, even in relapsed disease,” Dr. Mullighan said. “With such encouraging results, this combination should be evaluated clinically, especially in patients whose cancer is resistant to menin inhibition.”
Background
NUP98 fusion oncoproteins drive leukemogenesis in about 5% of pediatric AMLs, with the prevalence increasing in monocytic, megakaryoblastic, and erythroid AML. Most children with NUP98-rearranged AML relapse after standard therapy.
NUP98 has been found to have more than 30 different fusion partners, many of which have a DNA-binding homeodomain. These fusion oncoproteins drive chromatin remodeling and hematopoietic self-renewal.
Small molecule menin inhibitors have been able to displace NUP98 fusion oncoproteins from chromatin and extend survival in mouse models of NUP98-rearranged AML.
Study Findings
The researchers used genome editing to inactivate genes interacting with NUP98 fusion proteins to determine which ones the cancer depended on. MOZ/KAT6A and HBO1/KAT7, which help form a complex that activates pro-cancer gene expression, were singled out.
The study authors found that MYST histone acetyltransferases are molecular dependencies in NUP98-rearranged AML as the complex proteins associate with NUP98 fusion oncoproteins on chromatin and within condensates. Genetic inactivation or pharmacological inhibition of KAT6A/7 impairs the cell fitness of NUP98 rearrangements.
KAT6A/7 inhibition led to decreased global H3K23ac levels, displaced NUP98 from chromatin, myeloid cell differentiation, and decreased leukemic burden. KAT6A/7 inhibition was found to synergize with menin inhibition in NUP98-rearranged leukemia xenograft mouse models and it was effective in menin inhibitor–resistant cells.
“We found NUP98 fusions drive leukemia by assembling these proteins in a complex to switch on the expression of genes that turn normal cells into leukemia cells,” Dr. Mullighan said. “We showed these inhibitors can stop the assembly of the switch, preventing activation of these cancer-driving genes, which may be a novel therapeutic vulnerability in AML.”
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
