PML induces expression of ELANE-I60F. (A-B) Expression of ELANE in TPM showing upregulated expression in ELANE-I60F, but not ELANE-R103L and HAX1-W44X (data are derived from 2 independent clones and 2 independent experiments) (A), and increased levels of ELANE messenger RNA in ELANE-I60F HPCs, which is reduced to control levels when PML is absent (n = 3 independent experiments) (B). (C) Immunoblot showing PML-dependent NE protein abundance, with increased levels in ELANE-I60F cells. (D) Immunoblot of patient BM cells showing increased NE protein abundance in ELANE-mutant cells with predicted NE misfolding (I60F and P139L), but not others (I120T and S204TfsX11). (E) Quantification of immunofluorescence images showing increased, ELANE-I60F–driven numbers of PML-NBs. Data are pooled from 3 independent experiments and 3 independent ELANE-I60F–corrected clones resulting in; control: n = 126; ELANE-I60F: n = 144; ELANE-I60F corrected n = 442, where n = the number of cells. The red line indicates the median number of PML-NBs/cell for the control HPCs. (F) Immunoblot showing increased NE protein abundance in ELANE-I60F cells, which is reduced to control levels upon correction of the mutation, as shown in 2 independent clones. (G) GSEA comparing ELANE-I60F HPCs with corrected ELANE-I60F HPCs (2 independent experiments and 3 independent corrected clones) showing increased MYC, mTORC1, and cell cycle–related signatures in ELANE-I60F HPCs. ELANE PML^−/−, ELANE-I60F PML^−/−. *P < .05, **P < .01, ***P < .001.