Abstract
AbstractTranslocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.
Highlights
IntroductionAcute myeloid leukemia (AML) driven by chromosomal translocations involving the nucleoporin 98 (NUP98) gene on chromosome 11p15 is the most common genotype among children with relapsed and refractory disease, representing a high-risk group of patients with extremely poor outcomes.[1,2,3] NUP98 translocations generate NUP98 fusion proteins that join the N-terminal domain of NUP98 with various C-terminal partners that include epigenetic modifiers and transcription factors with homeobox domains such as the HOX genes.[4,5] Previous efforts to model NUP98-rearranged hematologic malignancies have revealed that NUP98-JARID1A, NUP98-NSD1, NUP98-HOXA9, and NUP98-HOXD13 fusion proteins are potent drivers of leukemia development.[6,7,8,9] While these fusions are potent oncoproteins, accompanying mutations in genes such as WT1 or FLT3 internal tandem duplications confer an even more dismal prognosis.[10]
We focused on nucleoporin 98 (NUP98)-HOXA9 and NUP98-JARID1A since the ability of these fusion proteins to transform mouse LSK cells without cooperating mutations had been previously described.[9,23]
Engraftment of LSK cells transduced with either NUP98-HOXA9 or NUP98-JARID1A fusion proteins resulted in relatively rapid onset of disease at 112 days and 85 days, respectively
Summary
Acute myeloid leukemia (AML) driven by chromosomal translocations involving the nucleoporin 98 (NUP98) gene on chromosome 11p15 is the most common genotype among children with relapsed and refractory disease, representing a high-risk group of patients with extremely poor outcomes.[1,2,3] NUP98 translocations generate NUP98 fusion proteins that join the N-terminal domain of NUP98 with various C-terminal partners that include epigenetic modifiers and transcription factors with homeobox domains such as the HOX genes.[4,5] Previous efforts to model NUP98-rearranged hematologic malignancies have revealed that NUP98-JARID1A, NUP98-NSD1, NUP98-HOXA9, and NUP98-HOXD13 fusion proteins are potent drivers of leukemia development.[6,7,8,9] While these fusions are potent oncoproteins, accompanying mutations in genes such as WT1 or FLT3 internal tandem duplications confer an even more dismal prognosis.[10]. NUP98 fusion proteins promote leukemogenesis through their interaction with histone-modifying chromatin complexes.[11,12,13] Previous studies have implicated histone methylation and acetylation at the Hoxa/b clusters, as well as the Meis[1] locus, as a mechanism that supports alterations in gene expression that promote leukemia development. Through its interaction with Wdr[8], the NUP98-NSD1 fusion recruits the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which deposits an activating mark on histone H3 lysine 4 (H3K4me3) across the HOXa cluster and at the Meis[1] promoter.[11] NUP98 fusions interact with the non-specific lethal (NSL) and mixedlineage leukemia (MLL1; known as KMT2A) chromatin complexes. NUP98-HOXA9 colocalizes with MLL1 at the Hoxa/b clusters, and loss of MLL1 delays onset of disease in a NUP98HOXA9 mouse leukemia model, demonstrating that MLL1 is a molecular dependency in NUP98-rearranged leukemia.[13]
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