All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment.

Meng Su,Jianshi Yu,Gabriel Ghiaur,Maureen A Kane,Jace W Jones,Richard J Jones,Salvador Alonso,Moray Campbell

doi:10.1371/journal.pone.0127790

Abstract

Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML.

Highlights

Acute myeloid leukemia (AML) is characterized by impaired differentiation and uncontrolled proliferation with subsequent accumulation of immature cells
We recently showed that bone marrow (BM) mesenchymal stroma protects normal hematopoietic stem cells (HSCs) from all-trans retinoic acid (atRA)-mediated differentiation through the expression of CYP26, the major mechanism of retinoid inactivation[25]
The early success seen with the introduction of atRA in treatment protocols of acute promyelocytic leukemia (APL) raised hope that differentiation therapy could change the face of current treatments in leukemia; this was further bolstered by evidence of atRA’s activity against most non-APL AMLs in vitro[7,8,9,10,11,12]

Summary

Introduction

Acute myeloid leukemia (AML) is characterized by impaired differentiation and uncontrolled proliferation with subsequent accumulation of immature cells (blasts). Even though the treatment results in AML have improved over the past 30 years, more than 50% of young adults and 90% of older patients die of their disease[1]. Advances in the treatment of one AML subtype, acute promyelocytic leukemia (APL), raised hopes that all-trans retinoic acid (atRA)based therapies might improve outcomes in other AML subtypes. In APL, the C-terminus of retinoic acid receptor α (RARα) on chromosome 17 is most often fused with N-terminus of promyelocytic leukemia protein (PML) on chromosome 15[2]. The resultant fusion protein, PLOS ONE | DOI:10.1371/journal.pone.0127790. The resultant fusion protein, PLOS ONE | DOI:10.1371/journal.pone.0127790 June 5, 2015

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