Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia

Abstract

The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In Npm1c/Dnmt3a mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting.

Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

“…Drawing on the gene expression similarity with MLL -rearranged leukemia, and the dependence of MLL rearrangements on their DNA-binding cofactor menin to exert an oncogenic effect, recent studies have shed more light into how NPM1c induces the aberrant expression of HOX genes [ 83 , 84 ]. Using CRISPR/Cas9 editing, AML with the mutated NPM1 gene was found to be dependent on menin and on MEIS1 [ 85 , 86 ]. Though this series of investigations established the central role of the MLL complex and HOX genes in causing this leukemia, the mechanism by which NPM1c interacts with these epigenetic regulators is still unknown.…”

“…Given the growing knowledge on the central role of HOX genes in NPM1c pathogenesis and the interaction with the MLL chromatin complex, recent studies have leveraged the use of small molecule inhibitors of the MLL co-factor menin to target NPM1 -mutated AML [ 106 , 107 , 108 ]. Using an inducible Npm1 single mutant and Npm1/Dnmt3a double mutant mouse model in addition to patient-derived xenograft models, Uckelmann and colleagues tested the effect of VTP-50469, a small molecule inhibitor of menin [ 86 ]. They demonstrated that menin inhibition induced the loss of MEIS1 expression and led to the significant differentiation of Npm1c leukemic cells in vitro, with a potent anti-leukemic activity on NPM1c in pre-leukemia and in overt leukemia.…”

Targeting Chromatin Complexes in Myeloid Malignancies and Beyond: From Basic Mechanisms to Clinical Innovation

“…Consequently, genetic inactivation or pharmacologic inhibition of DOT1L has been established as a tool to target the MLL-fusion driven transcriptional program [ 154 , 163 , 164 , 165 , 166 , 167 ]. Of note, other subtypes of leukemia that show a high dependency on wild-type MLL1, like NPM1-, DNMT3A-, and IDH1/2-mutated as well as NUP98-rearranged AML, have been shown to be likewise sensitive to inhibition of DOT1L [ 153 , 168 , 169 , 170 , 171 ]. Given the fact that DOT1L is not required in normal tissues, pharmacological inhibition of DOT1L could be a highly selective treatment strategy in MLL -rearranged and MLL-dependent leukemia.…”

Chromatin Complexes Maintain Self-Renewal of Myeloid Progenitors in AML: Opportunities for Therapeutic Intervention

“…Furthermore, wild-type MLL1 and, more specifically, its Menin-binding domain, were shown to be essential in NPM1c AML. Similar to their MLL -rearranged counterparts, NPM1c AML cells also show a reversal of their aberrant self-renewal properties in response to novel Menin inhibitors, and patient-derived xenograft models demonstrate dramatic responses to this approach ( Uckelmann et al., 2020 ). In addition to treating frank NPM1c AML, Menin-MLL inhibition can prevent the development of leukemia from preleukemic cells and rapidly eradicate preleukemic clones in a model of Npm1c mutant leukemia development ( Uckelmann et al., 2020 ).…”

“…Similar to their MLL -rearranged counterparts, NPM1c AML cells also show a reversal of their aberrant self-renewal properties in response to novel Menin inhibitors, and patient-derived xenograft models demonstrate dramatic responses to this approach ( Uckelmann et al., 2020 ). In addition to treating frank NPM1c AML, Menin-MLL inhibition can prevent the development of leukemia from preleukemic cells and rapidly eradicate preleukemic clones in a model of Npm1c mutant leukemia development ( Uckelmann et al., 2020 ). These promising results demonstrate that therapeutic approaches designed to target MLL-fusion complexes can also be used in wild-type MLL-dependent cancers and premalignant cells, as they depend on similar epigenetic machinery for the regulation of neoplastic gene expression programs.…”