Chemogenomic Landscape of RUNX1-mutated AML Reveals Importance of RUNX1 Allele Dosage in Genetics and Glucocorticoid Sensitivity

Abstract

-mutated () acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup. RNA-sequencing of 47 primary AML specimens was performed and sequencing results were compared to those of wild-type samples. Chemical screens were also conducted using specimens to identify compounds selectively affecting the viability of AML. We show that samples with no remaining wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating expression in human AML cells. Our findings show the profound impact of allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. .

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

“…The enrichment of RUNX1 mutations in pDC-AML implies a crucial role of this genetic event and downstream altered gene regulatory networks in pDC differentiation. Prior studies have shown that pDCrelated transcription factors are highly expressed in RUNX1 mutated AML (64)(65)(66), which is further supported by our data. Our study also provides direct evidence that the leukemic blasts from RUNX1 mutated AML are primed to differentiate into pDCs.…”

Dexamethasone in hyperleukocytic acute myeloid leukemia

“…A recent pre-clinical study demonstrated that AML cells with RUNX1 mutations were sensitive to glucocorticoids while earlier in vitro studies suggested an antileukemic activity in AML with the t(8;21)/ RUNX1-RUNX1T1 translocation. 21 , 22 To find out whether other molecular subgroups could benefit from glucocorticoids, we first tested the in vitro activity of dexamethasone against AML cell lines with various genetic backgrounds. As expected, dexamethasone had no significant activity as a single agent in most AML cell lines cultured in suspension ( Figure 4A ).…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Results show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, which may lead to drug repurposing and improved disease characterization [79].…”