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Review
. 2020 Oct;19(20):2573-2588.
doi: 10.1080/15384101.2020.1810402. Epub 2020 Sep 8.

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

Chi H Nguyen  1   2 , Alexander M Grandits  1   2 , Louise E Purton  3 , Heinz Sill  4 , Rotraud Wieser  1   2
Affiliations
Review

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

Chi H Nguyen et al. Cell Cycle. 2020 Oct.

Abstract

Acute myeloid leukemia (AML) is an aggressive, often fatal hematopoietic malignancy. All-trans retinoic acid (atRA), one of the first molecularly targeted drugs in oncology, has greatly improved the outcome of a subtype of AML, acute promyelocytic leukemia (APL). In contrast, atRA has so far provided little therapeutic benefit in the much larger group of patients with non-APL AML. Attempts to identify genetically or molecularly defined subgroups of patients that may respond to atRA have not yielded consistent results. Since AML is a stem cell-driven disease, understanding the effectiveness of atRA may require an appreciation of its impact on AML stem cells. Recent studies reported that atRA decreased stemness of AML with an FLT3-ITD mutation, yet increased it in AML1-ETO driven or EVI1-overexpressing AML. This review summarizes the role of atRA in normal hematopoiesis and in AML, focusing on its impact on AML stem cells.

Keywords: AML; FLT3; MECOM; atRA; hematopoietic stem cell; leukemia stem cell.

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Figures

Figure 1.
Figure 1.
Role of all-trans retinoic acid (atRA) in hematopoietic stem cells (HSCs). Blue box summarizes key experiments leading to the conclusion that atRA negatively affects HSCs. Green boxes summarize key experiments leading to the conclusion that atRA positively affects HSCs. RAR, retinoic acid receptor; SCID, mice with severe combined immunodeficiency; ST, short term; LT, long term. Human cells are depicted in purple and murine cells in gray. The number of symbols in the serial transplantation assay is not meant to indicate the actual number of transplantations
Figure 2.
Figure 2.
Effects of all-trans retinoic acid (atRA) on leukemic blasts of genetically or molecularly defined subgroups of AML. Yellow boxes summarize inhibition of anti-leukemic effects of atRA (note, however, that primary AML1-ETO positive blasts were found to be atRA sensitive in an independent study; see main text). Green boxes summarize anti-leukemic effects of atRA. Human cells are depicted in purple and murine cells in gray. IC, isocitrate; α-KG, α-ketoglutarate; 2-HG, 2-hydroxyglutarate; NSG, non-obese diabetic severe combined immunodeficiency IL2Rgnull mice; DNR, daunorubicin; Doxo, doxorubicin
Figure 3.
Figure 3.
Effects of all-trans retinoic acid (atRA) on AML stem cells. Green box summarizes anti-leukemic effects of atRA; yellow boxes summarize pro-leukemic effects of atRA; gray boxes summarize absence of an effect of atRA. LC, leukemic cells; pLC, preleukemic cells; LSK cells, lin− Sca1+ c-Kit+ cells (HSC enriched); CMPs, common myeloid progenitor cells; LSCs, leukemic stem cells; LSCe, LSC enriched cells; act., activity. Numbers of symbols in serial replating or transplantation assays are not meant to indicate the actual numbers of repetitions
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