Dataset Information

Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RAR? and PLZF/RAR?.

ABSTRACT: Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RAR?, PLZF/RAR?, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RAR? and PLZF/RAR? or AML-1/ETO activate Wnt signaling by upregulating ?-catenin and ?-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RAR?-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both ?-catenin and ?-catenin in X-RAR?-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RAR?-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RAR?, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

SUBMITTER: Steinert G

PROVIDER: S-EPMC3139642 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

Steinert Gunnar G Oancea Claudia C Roos Jessica J Hagemeyer Heike H Maier Thorsten T Ruthardt Martin M Puccetti Elena E

PloS one 20110719 7

Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of ...[more]

PMID: 21811629

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Project description:Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RAR? and RAR? have opposing effects on K5+ cell cycle progression and cell distribution. RAR? negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RAR? is necessary but not sufficient to positively maintain K5+ cells, as agonism of RAR? alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RAR? agonism and RAR? inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RAR? and RAR? reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RAR? may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool.RAR? and RAR? reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.

Project description:The oncogenic fusion protein PML/RAR is expressed in most cases of acute promyelocytic leukemia (APL). In transgenic models, PML/RAR is able to induce a preleukemic state. However, it is not sufficient to induce leukemia, which develops with low frequency (~50%) and long latency (about 1 year). These data indicate that secondary genetic cooperating alterations are required in order to induce leukemia. In an effort to identify the genes that cooperate in the leukemogenesis PML/RAR-dependent, we performed an insertional mutagenesis screening infecting the PML/RAR KI mice with Moloney Murine Leukemia Virus (MLV). The infection of the PML/RAR KI mice significantly accelerated the onset (~6 months) and increased the penetrance (~75% of infected animals) of the leukemia. To identify genes mutated by the proviral integrations, flanking sequences of the retrovirus insertions were cloned by IPCR and analysed by parallel sequencing. We sequenced DNAs from the spleen of 48 independent leukemic mice. After filtering, ~133,000 reads were univocally mapped onto the mouse genome. Of them, ~131,000 were present more than once in the DNA from the same mouse and produced a total of 1,707 independent genomic insertions (retroviral insertion sites - RISs). To identify chromosomal regions that are frequently mutated by retrovirus insertions (common insertion sites; CISs), we evaluated the density of RISs distribution over the mouse genome, using statistical approaches that calculate the significance of RISs occurrence (p<0.05) within specific genomic regions (Monte Carlo simulation or Kernel Convolution). The two different approaches identified the same set of 221 CISs. Finally, we identified 271 genes putatively targeted by retroviral insertions in the 221 CISs. These putative targets appeared to be enriched in genes identified as relevant cancer-genes in different tumor types. Moreover, from a biological point of view, our screening was performed in saturating conditions. Therefore, to our knowledge, our is the first report of an exhaustive list of virtually all the mouse genes that functionally cooperate with PML/RAR in the induction of APL.

Dataset Information

Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RAR? and PLZF/RAR?.

Publications

Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

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