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Review
. 2014 Jul;100(1):18-26.
doi: 10.1007/s12185-014-1518-x. Epub 2014 Feb 1.

The role of PML in hematopoietic and leukemic stem cell maintenance

Fumio Nakahara  1 , Cary N Weiss, Keisuke Ito
Affiliations
Review

The role of PML in hematopoietic and leukemic stem cell maintenance

Fumio Nakahara et al. Int J Hematol. 2014 Jul.

Abstract

The tumor suppressor promyelocytic leukemia (PML) was first identified as a component of PML-RARα fusion protein, one of the initiating cytogenetic abnormalities in acute promyelocytic leukemia. PML is now known to have diverse functions regulating the DNA-damage response, apoptosis, senescence, and angiogenesis. Recent investigations have identified PML as a regulator of metabolic pathways in stem cell compartments, including the hematopoietic system, and have provided researchers with new strategies for controlling stem cell maintenance and differentiation. Studies of PML in leukemia-initiating cells demonstrate that PML is also an essential component of their maintenance, which has drawn tremendous attention to PML from scientists in various stem cell fields. Here, we review research into PML and its associated pathways, including recent studies of PML as it relates to stem cell biology, as well as our finding that PML regulates fatty acid oxidation, which is essential to the maintenance of normal hematopoietic stem cells. We also discuss the therapeutic potential of controlling PML-associated pathways. In particular, we describe promising evidence for the use of arsenic trioxide in the treatment of chronic myeloid leukemia.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Structure of the PML–RARα fusion protein. PML–RARα encodes the RING finger, B boxes and at least two coiled coil (RBCC) domains of PML, and most portions of RARα including the B through F domains. B domain, transcriptional activation domain (AF-1); C domain, DNA binding site which contains two C2C2 zinc finger motifs and RARα binds to retinoic acid response element (RARE) located in the promoters of many genes through this domain; D, hinge region; E, transcriptional activation domain (AF-2); F, function unknown. The PML–RARα fusion protein induces a block of hematopoietic differentiation. When all-trans retinoic acid (ATRA) is administered, it disassociates corepressor from the PML–RAR/ RXR complex and recruits coactivator, promoting RARα-target gene transcription to overcome the differentiation block and enables leukemic cells to differentiate in APL, leading to their exhaustion. On the other hand, arsenic trioxide (As2O3) induces degradation of PML and the fusion protein PML–RARα through sumoylation, and promotes differentiation of leukemic cells in APL
Fig. 2
Fig. 2
The many functions of promyelocytic leukemia nuclear bodies and PML as a negative regulator of the PI3-kinase/Akt/mTOR pathway. a Promyelocytic leukemia nuclear bodies (PML-NBs) regulate diverse cellular functions, including the DNA-damage response, by storing and releasing checkpoint proteins and repair proteins following DNA damage; metabolism necessary for stem cell maintenance; cellular apoptosis and senescence; and angiogenesis. PML-NBs orchestrate these many functions through post-translational modification of proteins, including sumoylation, acetylation and phosphorylation; regulation of nuclear activities, such as transcription and chromatin organization; and the identification and storage of proteins. b Aberrant activation of the PI3-kinase/Akt/mTOR pathway leads to the depletion of HSCs, which enter the cell cycle and are quickly exhausted. This pathway is negatively regulated by nuclear PML at several levels. PML maintains the PTEN tumor suppressor in the nucleus and inactivates phosphorylated AKT by recruiting an Akt phosphatase. PML also suppresses mTOR by inhibiting its association with Rheb, through physical interaction and accumulation of mTOR in the nucleus. Rheb, Ras homolog enriched in brain; TSC, tuberous sclerosis complex
Fig. 3
Fig. 3
PML regulates asymmetric division and stem cell maintenance. PML induces deacetylation of PGC1α, which leads to the activation of peroxisome proliferator-activated receptor (PPAR) signaling and the expression of fatty acid oxidation (FAO) genes. FAO increases asymmetric cell division in HSCs, enabling their self-renewal and maintenance. When FAO is pharmacologically inhibited by etomoxir, HSCs undergo symmetric commitment and are exhausted
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