By Michael Linenberger, MD
2009-01-01
Dr. Linenberger indicated no relevant conflicts of interest.
Ito K, Bernardi R, Morotti A, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008;453:1072-8.
Leukemia-initiating cells (LICs; also known as leukemia stem cells)
have been identified in myeloid and lymphoid acute and chronic leukemia
subtypes. Like normal hematopoietic stem cells (HSCs), LICs are
pluripotent, self-renewing, phenotypically primitive and mitotically
quiescent. Their non-cycling status and inherent or acquired drug
resistance mechanisms allow them (like HSCs) to escape conventional and
targeted therapies that effectively kill the more mature, proliferating
leukemia cell progeny. LICs, therefore, serve as a reservoir for
disease persistence and relapse. One theoretic approach to eliminate
LICs and improve cure rates is to induce their entry into cell cycle to
promote differentiation and clonal extinction and/or to render them
susceptible to cytotoxic agents.
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The study by Ito, et al. was prompted by observations of high levels
of promyelocytic leukemia (PML) tumor suppressor protein in blast cells
in 88 percent of chronic-phase CML cases and an association between
high-blast PML expression and poor response to imatinib. They sought to
understand the role of PML in normal HSC maintenance and whether it
might serve as a useful therapeutic target in LICs. High PML mRNA and
protein levels were found in normal human and murine HSCs but not in
more committed progenitors. PML absence (in Pml–/– mice) or pharmacologic down-modulation (using arsenite arsenic trioxide [As2O3])
was associated with increased cell cycling and ultimate "exhaustion" of
HSCs as manifested by compromised long-term engraftment post-transplant
and impaired reconstitution with serial transplantation. CML LICs were
generated by transduction of p210BCR-ABL into HSCs from Pml+/+ and Pml–/– mice. Culture studies and in vivo
models revealed that PML was required for LIC mitotic quiescence,
long-term maintenance, and aggressive disease phenotype in serially
transplanted mice. Additional studies indicated that PML acts as a
repressor of mTOR and that mTOR super-activation can impair HSC and LIC
maintenance, but inhibition of mTOR with rapamycin accentuates in vivo lethality of Pml+/+ CML LICs. Like HSCs, As2O3 induced quiescent Pml+/+ LICs into cell cycle and led to clonal extinction during serial transplantation.
As2O3 also profoundly augmented cytosine
arabinoside (Ara-C)-induced apoptosis, but the effects on normal murine
HSCs were modest compared to LICs. Thus, mice with experimental CML
could eventually be "cured." In vitro studies with human cells showed similar pronounced and preferential effects of As2O3
alone and in combination with Ara-C on PML expression, cell cycle
entry, maintenance, and drug susceptibility in primary CML LICs
compared to normal HSCs.
This study provides a number of key insights: 1) PML
is an essential regulator of HSC mitotic quiescence and long-term
maintenance; 2) PML is required for CML LIC quiescence and disease
persistence in murine models; and 3) PML down-regulation in CML LICs by
As2O3, a commercially available drug,
preferentially and potently induces entry into cell cycle and drug
sensitization (see Figure), thereby providing an immediately testable
therapeutic approach.
Enthusiasm must be tempered by the fact that genomic instability in CML LICs leads to additional molecular lesions besides BCR-ABL1,
and, therefore, pharmacologic PML manipulation may not yield the
predicted effects in clinical trials. To fully exploit PML as a
therapeutic target, it will also be necessary to define the relevant
mechanistic pathways and proteins (in addition to mTOR) involved in HSC
maintenance and LIC pathophysiology. This will be challenging because
PML is a critical component of the PML nuclear body that regulates DNA
damage responses, apoptosis, cellular senescence, and angiogenesis
through a variety of complex multiprotein interactions that are not yet
well characterized. Lastly, it will be important to determine whether
PML plays a similar role in LICs in other leukemias, or in
non-hematologic tissue stem cells and cancer-initiating cells, and to
explore potential therapeutic applications beyond CML.
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