Abstract
DNA-methyltransferase 3A (DNMT3A) mutations belong to the most frequent genetic aberrations found in adult acute myeloid leukemia (AML). Recent evidence suggests that these mutations arise early in leukemogenesis, marking leukemic progenitors and stem cells, and persist through consolidation chemotherapy, providing a pool for AML relapse. Currently, there are no therapeutic approaches directed specifically against this cell population. To unravel therapeutically actionable targets in mutant DNMT3A-driven AML cells, we have performed a focused RNAi screen in a panel of 30 primary AML samples, all carrying a DNMT3A R882 mutation. As one of the strongest hits, we identified MDM4 as a gene essential for proliferation of primary DNMT3AWT/R882X AML cells. We analyzed a publicly available RNA-Seq dataset of primary normal karyotype (NK) AML samples and found a trend towards MDM4 transcript overexpression particularly in DNMT3A-mutant samples. Moreover, we found that the MDM2/4 inhibitor ALRN-6924 impairs growth of DNMT3AWT/R882X primary cells in vitro by inducing cell cycle arrest through upregulation of p53 target genes. Our results suggest that MDM4 inhibition is a potential target in NK-AML patients bearing DNMT3A R882X mutations.
Highlights
Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system
Recent studies in primary cells from AML patients have shown that the DNA-methyltransferase 3A (DNMT3A) R882 mutation marks immature cells that are resistant to chemotherapy and represent a reservoir for AML relapse [5]
We have shown that mutant DNMT3A is not required for in vitro survival and proliferation of leukemic blasts by correcting the R882H mutation in SET2 cells with an adenine base editor
Summary
Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system It is characterized by uncontrolled proliferation of immature blood cells, called leukemic blasts, caused by the impairment of differentiation programs in hematopoietic stem and progenitor cells (HSPCs). Conventional chemotherapy treatment can efficiently eliminate the leukemic blasts; it typically fails to eradicate the immature, quiescent populations of leukemic progenitors [1,2] These can drive leukemogenesis anew, creating a risk of disease recurrence (relapse), often with a more aggressive phenotype and a worse prognosis [3]. Scientific efforts have been directed towards the development of targeted therapies that would eliminate these immature cell populations and prevent recurrence of the disease in patients in remission. Recent studies in primary cells from AML patients have shown that the DNMT3A R882 mutation marks immature cells that are resistant to chemotherapy and represent a reservoir for AML relapse [5]. There is a clinical need for discovering vulnerabilities of this cell population that can be exploited as a therapeutic approach
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