All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism.

Dalyia N Benjamin,Kristian B Laursen,Mary R Cahill,Lorraine J Gudas,Nina Orfali,Sharon L Mckenna,Tracey R O’Donovan,Nigel P Mongan

doi:10.3389/fonc.2022.848517

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy.

Highlights

Acute myeloid leukemia (AML) is a group of haematopoietic disorders characterised by a failure of differentiation in myeloid progenitor cells
We investigated whether valproic acid (VPA) alone and in combination with all-trans-retinoic acid (ATRA) could induce differentiation in ATRA sensitive and resistant acute promyelocytic leukemia (APL) cell lines (NB4, NB4R) (Figure 1 and Supplementary Figure 1) and in a non-APL, differentiation resistant myeloid leukemia cell line (THP-1) (Supplementary Figures 2A, B)
Cells were treated with Valproic acid (VPA) (1 mM) or ATRA (1 μM) alone or in combination for 72 hours

Summary

Introduction

Acute myeloid leukemia (AML) is a group of haematopoietic disorders characterised by a failure of differentiation in myeloid progenitor cells. The outcome for adults with AML remains poor with a 5-year survival rate of ~40% for younger patients (18–60 years) and until recently was as low as ~10% for patients above the age of 60 years [2, 3]. While therapies have advanced in the last 5 years [4], there remains an urgent need for better, well tolerated, outpatient-based management strategies in older adults. One particular subgroup of AML, acute promyelocytic leukemia (APL), which represents about 5-10% of cases, has undergone a radical improvement in treatment outcomes in the last 30 years with the advent of differentiation therapy. Current chemotherapy-free treatment regimens for low to intermediate-risk APL, based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), achieve complete remission rates exceeding 90% and overall survival of 85-99% [5]

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Conclusion