Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

Abstract

The mainstay of acute myeloid leukemia (AML) treatment still relies on traditional chemotherapy, with a survival rate of approximately 30% for patients under 65 years of age and as low as 5% for those beyond. This unfavorable prognosis primarily stems from frequent relapses, resistance to chemotherapy, and limited approved targeted therapies for specific AML subtypes. Around 70% of all AML cases show overexpression of the transcription factor HOXA9, which is associated with a poor prognosis, increased chemoresistance, and higher relapse rates. However, direct targeting of HOXA9 in a clinical setting has not been achieved yet. The dysregulation caused by the leukemic HOXA9 transcription factor primarily results from its binding activity to DNA, leading to differentiation blockade. Our previous investigations have identified two HOXA9/DNA binding competitors, namely DB1055 and DB818. We assessed their antileukemic effects in comparison to HOXA9 knockdown or cytarabine treatment. Using human AML cell models, DB1055 and DB818 induced in vitro cell growth reduction, death, differentiation, and common transcriptomic deregulation but did not impact human CD34+ bone marrow cells. Furthermore, DB1055 and DB818 exhibited potent antileukemic activities in a human THP‐1 AML in vivo model, leading to the differentiation of monocytes into macrophages. In vitro assays also demonstrated the efficacy of DB1055 and DB818 against AML blasts from patients, with DB1055 successfully reducing leukemia burden in patient‐derived xenografts in NSG immunodeficient mice. Our findings indicate that inhibiting HOXA9/DNA interaction using DNA ligands may offer a novel differentiation therapy for the future treatment of AML patients dependent on HOXA9.

How to put a hex on HOX

“…A new and potentially very promising approach to target HOXA9 is described by David‐Cordonnier and colleagues in this issue of Hemasphere . 8 This work is based on a previous screen performed by the authors where they searched a library of heterocyclic diamidines that are known to have minor grove DNA binding capacity. They identified two compounds (DB818, DB1055) with an affinity for the common core HOX binding sequence 5′‐ATTTA‐3′.…”

“…Most remarkably, and despite the undisputed importance of HOXA9 also in normal hematopoietic development, the authors could not detect any detrimental effect of DB818/1055 treatment on normal CD34+ hematopoietic stem cells (HSCs) in vitro. 8 …”

“…In addition, competition of DB818/1055 and HOXA9 for DNA could be convincingly demonstrated in biochemical assays. 8 …”

“…In these experiments, DB1055 could reduce the outgrowth of human leukemia comparable to a cytosine arabinoside test treatment. 8 …”

“…In addition, competition of DB818/1055 and HOXA9 for DNA could be convincingly demonstrated in biochemical assays. 8 In a further series of experiments, DB818/1055 was compared to the knockdown of HOXA9 in a THP-1 cell line transplantation model where both approaches affected a moderate but significant prolongation of disease-free survival. Finally, the in vivo efficacy of DB818/1055 was also visible in xenotransplants with injected patient blast cells.…”