Newly Identified Roles of PML in Stem Cell Biology

Kyoko Ito,Keisuke Ito

doi:10.3389/fonc.2013.00050

Abstract

It has long been believed that the tumor suppressor promyelocytic leukemia (PML), the core component of the nuclear substructures known as the PML-nuclear bodies, plays a key part in acute PML (APL), as it is first cloned at the breakpoint of the t(15;17) translocation typical of that disease. Research over the past decade, however, has radically changed our view of how this tumor suppressor is regulated, how it can be therapeutically targeted, and how it functions in a number of tissue systems. One noteworthy recent study, for instance, revealed that PML regulates the activation of fatty acid metabolism, and that this metabolic reprograming plays an essential role in cancer biology and stem cell biology through the control it exerts over stem cell fate decisions. These findings sparked exciting new investigations of PML as a critical “rheostat” responsible for fine-tuning tissue homeostasis, and thus created at the intersection of cancer and stem cell biology a new field of study with important therapeutic implications.

Highlights

Unlike the well-established roles of promyelocytic leukemia (PML) and PML-nuclear bodies (NBs) in solid tumors and leukemia pathogenesis [which are effected through modulation of the activity of p53 (Bernardi et al, 2004), Atk (Trotman et al, 2006), mTOR, HIF1α (Bernardi et al, 2006), or mitochondrial regulatory pathways (Giorgi et al, 2010)], little is known about the role of this tumor suppressor in stem cell biology or the mechanisms of its regulation of cancer metabolism
Critical modulators and effectors of this pathway, such as PTEN and the forkhead O (FoxO) family, have recently been implicated in the stem cell biology of the hematopoietic system (Trotman et al, 2006; Yilmaz et al, 2006; Zhang et al, 2006; Miyamoto et al, 2007; Tothova et al, 2007; Guo et al, 2008; Ito et al, 2008), where improper Akt-mTorc1 signaling can lead to profound defects in the maintenance of hematopoietic stem cells (HSCs)
We further defined a critical role for PML in the maintenance of leukemia-initiating cells (LICs) in disease models of chronic myeloid leukemia (CML), and presented a new therapeutic approach based on targeting quiescent LICs by pharmacological inhibition of PML

Summary

Introduction

Unlike the well-established roles of PML and PML-NBs in solid tumors and leukemia pathogenesis [which are effected through modulation of the activity of p53 (Bernardi et al, 2004), Atk (Trotman et al, 2006), mTOR, HIF1α (Bernardi et al, 2006), or mitochondrial regulatory pathways (Giorgi et al, 2010)], little is known about the role of this tumor suppressor in stem cell biology or the mechanisms of its regulation of cancer metabolism. We recently defined a critical role for PML in the stem cells of the hematopoietic system (Ito et al, 2008), and demonstrated that deletion of Pml leads to loss of quiescence in HSCs, resulting in their transient amplification and subsequent exhaustion.

Results

Conclusion