Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia

Guibal, Florence; Alberich-Jordà, Meritxell; Hirai, Hideyo; Ebralidze, Alexander K.; Levantini, Elena; Ruscio, Annalisa Di; Zhang, Pu; Santana-Lemos, Bárbara A.; Neuberg, Donna; Wagers, Amy J.; Rego, Eduardo Magalhães; Tenen, Daniel G.

doi:10.1182/blood-2008-10-182071

Cited by 125 publications

(122 citation statements)

References 55 publications

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“…These results are supported by our recent findings in mCG-PR mice, in which we have demonstrated that PML-RARA is expressed and functional in the KLS compartment (Welch et al, unpublished observations). Both results contradict the current paradigm, which suggests that PML-RARA transforms a committed myeloid precursor (i.e., a promyelocyte) by being expressed at that stage of development (26)(27)(28)(29). This is clearly not the case.…”

Section: Discussioncontrasting

confidence: 58%

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

Welch¹,

Yuan²,

Ley³

2011

J. Clin. Invest.

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Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that generates the fusion protein promyelocytic leukemia-retinoic acid receptor α (PML-RARA) in nearly all cases. Multiple prior mouse models of APL constitutively express PML-RARA from a variety of non-Pml loci. Typically, all animals develop a myeloproliferative disease, followed by leukemia in a subset of animals after a long latent period. In contrast, human APL is not associated with an antecedent stage of myeloproliferation. To address this discrepancy, we have generated a system whereby PML-RARA expression is somatically acquired from the mouse Pml locus in the context of Pml haploinsufficiency. We found that physiologic PML-RARA expression was sufficient to direct a hematopoietic progenitor self-renewal program in vitro and in vivo. However, this expansion was not associated with evidence of myeloproliferation, more accurately reflecting the clinical presentation of human APL. Thus, at physiologic doses, PML-RARA primarily acts to increase hematopoietic progenitor self-renewal, expanding a population of cells that are susceptible to acquiring secondary mutations that cause progression to leukemia. This mouse model provides a platform for more accurately dissecting the early events in APL pathogenesis. IntroductionMore than 95% of acute promyelocytic leukemia (APL; FAB-M3) cases are associated with the recurrent t(15;17)(q22:q11) translocation, which results in the expression of a fusion transcript promyelocytic leukemia-retinoic acid receptor α (PML-RARA), inconsistent expression of a reciprocal fusion product (RARA-PML), and haploinsufficiency for both PML and RARA (1, 2). Although APL has served as an important model disease for understanding leukemogenic pathways directed by a specific translocation, the precise mechanisms by which t(15;17) initiates leukemia remain unknown.Several mouse models have been used to study the mechanisms by which PML-RARA causes transformation (reviewed in refs. 3, 4). These models have used viral transduction, transgenic, and knockin strategies; regulatory sequences from the MRP8 gene (also known as S100 calcium binding protein A8 [S100A8]) and human and murine cathepsin G (CTSG and Ctsg, respectively) genes have been used to direct the expression of PML-RARA to the myeloid compartment (5-8), where can cause a myeloproliferative disease and APL after a long latent period.However, there are many issues with existing mouse models of APL that must be addressed to fully understand how PML-RARA works. (a) The dose of PML-RARA is known to be important for AML penetrance, but no model to our knowledge has yet expressed PML-RARA from the endogenous Pml locus. This has not previously been attempted, since Pml is ubiquitously expressed, and since widespread expression of PML-RARA during development causes embryonic lethality (9, 10). (b) t(15;17) is a somatically acquired event, but all prior models have used constitutive PML-RARA expression, raising the possibility that hematopoietic cells may have a...

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Section: Discussioncontrasting

confidence: 58%

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

Welch¹,

Yuan²,

Ley³

2011

J. Clin. Invest.

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“…17,29 Recently, in APL leukemic cells a sub-population enriched in leukemia-initiating cells has been identified, which showed simultaneous expression of more The coiled-coil domain of PML drives leukemogenesis M Occhionorelli et al mature differentiation markers (such as, Gr1), and stem cell markers (such as, c-Kit). 30,31 Indeed, PR, CCR and GCR cells recovered from the third plating showed the co-expression of c-Kit/Gr-1 markers (Figure 4b). 1 Taken together, these results indicate that all chimeric proteins showed a similar biological response in vitro, though GCR was unable to interact with PML and disrupt endogenous NBies.…”

Section: Resultsmentioning

confidence: 96%

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha

Occhionorelli¹,

Santoro²,

Pallavicini³

et al. 2011

Leukemia

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In acute promyelocytic leukemia (APL) the retinoic acid receptor alpha (RARa) becomes an oncogene through the fusion with several partners, mostly with promyelocytic leukemia protein (PML), all of which have in common the presence of a self-association domain. The new fusion proteins, therefore, differently from the wild-type RARa, which forms only heterodimers with retinoic X receptor alpha, are also able to homooligomerize. The presence of such a domain has been suggested to be crucial for the leukemogenic potential of the chimeric proteins found in APL blasts. Whether or not any selfassociation domain is sufficient to bestow a leukemogenic activity on RARa is still under investigation. In this work, we address this question using two different X-RARa chimeras, where X represents the coiled-coil domain of PML (CC-RARa) or the oligomerization portion of the yeast transcription factor GCN4 (GCN4-RARa). We demonstrate that in vitro both proteins have transforming potential, and recapitulate the main PML-RARa biological properties, but CC-RARa is uniquely able to disrupt PML nuclear bodies. Indeed, in vivo only the CCRARa chimera induces efficiently APL in a murine transplantation model. Thus, the PML CC domain represents the minimal structural determinant indispensable to transform RARa into an oncogenic protein.

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“…25,26 Indeed this notion is supported by a recent study showing that PML-RARA conduct partial silencing of CEPBA target genes through DNA methylation of its promoter regions. 42 The promoter analysis also showed that genes upregulated in APL cells versus PMs contained a significant enrichment of binding sites for TFs that propagate proliferation, mobilization and self-renewal of HSCs/LSCs. Among these we identified binding sites for NF-kB suggesting that enhanced activation of NF-kB target genes (Supplementary Table 3) might contribute to malignant transformation in APL.…”

Section: Discussionmentioning

confidence: 96%

“…This hypothesis is supported by recent studies showing that LSCs in murine APL models have a morphology and an immunophenotype similar to that of normal PMs. 42,44 To identify drug candidates that might be used as supplements in current APL treatment protocols, we searched for compounds that generated signatures in the HL-60 leukemia cell line, which reversed our APL and stemness signatures and induced an ATRA signature in APL cells. The rationale for this strategy is to identify compounds that inhibit cellular maintenance and self-renewal by downregulation of APL and stemness genes while at the same time promoting differentiation through upregulation of ATRA-dependent genes.…”

Section: Discussionmentioning

confidence: 99%

A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

et al. 2010

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Chromosomal translocations of transcription factors generating fusion proteins with aberrant transcriptional activity are common in acute leukemia. In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic-acid receptor alpha (PML-RARA) fusion protein, which emerges as a consequence of the t(15;17) translocation, acts as a transcriptional repressor that blocks neutrophil differentiation at the promyelocyte (PM) stage. In this study, we used publicly available microarray data sets and identified signatures of genes dysregulated in APL by comparison of gene expression profiles of APL cells and normal PMs representing the same stage of differentiation. We next subjected our identified APL signatures of dysregulated genes to a series of computational analyses leading to (i) the finding that APL cells show stem cell properties with respect to gene expression and transcriptional regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost. In a broader perspective, our study provides strong evidence that genomic strategies might be used in a clinical setting to prospectively identify candidate drugs that subsequently are validated in vitro to define the most effective drug combination for individual cancer patients on a rational basis.

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Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia

Cited by 125 publications

References 55 publications

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha

A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

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