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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 G, Oancea C, Roos J, Hagemeyer H, Maier T, Ruthardt M, Puccetti E - PLoS ONE (2011)

Bottom Line: 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.Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling.We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Goethe-University, Frankfurt, Germany.

ABSTRACT
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 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-RARα-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 β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, 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.

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Effect of SSi on PML/RARα-mediated aberrant long-term stem cell capacity in murine HSC.(A) Experimental strategy for studying the LT-HSC capacity of PML/RARα-expressing HSCs. Sca1+/lin- BM cells from CD45.1+ mice were infected with the indicated retroviruses and maintained for one week in liquid culture with the indicated growth factors in the presence/absence of 40 µM SSi. The cells were co-transplanted with CD45.2+ BM cells into lethally (11 Gy) irradiated CD45.2+ recipient mice. (B) Donor chimerism 8 months after transplantation was used to determine LT-HSC capacity in the BM and spleen. Statistical significance was determined using the Log-rank (Mantel-Cox) test (* <0.05; ** <0.01).
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pone-0022540-g007: Effect of SSi on PML/RARα-mediated aberrant long-term stem cell capacity in murine HSC.(A) Experimental strategy for studying the LT-HSC capacity of PML/RARα-expressing HSCs. Sca1+/lin- BM cells from CD45.1+ mice were infected with the indicated retroviruses and maintained for one week in liquid culture with the indicated growth factors in the presence/absence of 40 µM SSi. The cells were co-transplanted with CD45.2+ BM cells into lethally (11 Gy) irradiated CD45.2+ recipient mice. (B) Donor chimerism 8 months after transplantation was used to determine LT-HSC capacity in the BM and spleen. Statistical significance was determined using the Log-rank (Mantel-Cox) test (* <0.05; ** <0.01).

Mentions: To determine whether SSi interferes with the capacity of X-RARα to maintain long-term stem cell (LT-HSC) capacity, we performed a CRA assay [38] on PML/RARα-positive Sca1+/lin− HPCs cultured for seven days in the presence/absence of 40 µM SSi (Figure 7A). The population density of LT-HSC was assessed via CD45.1/CD45.2 chimerism, which demonstrates the capacity of the PML/RARα-positive CD45.1+ donor cells to compete the reconstitution of hematopoiesis by CD45.2+ BM cells in lethally irradiated CD45.2+ recipients (Figure 7A). Upon exposure to SSi, we found that after 8 months, the proportion of PML/RARα-positive HPCs was significantly reduced in the BM and spleens of recipient mice compared with untreated controls (Figure 7B).


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

Steinert G, Oancea C, Roos J, Hagemeyer H, Maier T, Ruthardt M, Puccetti E - PLoS ONE (2011)

Effect of SSi on PML/RARα-mediated aberrant long-term stem cell capacity in murine HSC.(A) Experimental strategy for studying the LT-HSC capacity of PML/RARα-expressing HSCs. Sca1+/lin- BM cells from CD45.1+ mice were infected with the indicated retroviruses and maintained for one week in liquid culture with the indicated growth factors in the presence/absence of 40 µM SSi. The cells were co-transplanted with CD45.2+ BM cells into lethally (11 Gy) irradiated CD45.2+ recipient mice. (B) Donor chimerism 8 months after transplantation was used to determine LT-HSC capacity in the BM and spleen. Statistical significance was determined using the Log-rank (Mantel-Cox) test (* <0.05; ** <0.01).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3139642&req=5

pone-0022540-g007: Effect of SSi on PML/RARα-mediated aberrant long-term stem cell capacity in murine HSC.(A) Experimental strategy for studying the LT-HSC capacity of PML/RARα-expressing HSCs. Sca1+/lin- BM cells from CD45.1+ mice were infected with the indicated retroviruses and maintained for one week in liquid culture with the indicated growth factors in the presence/absence of 40 µM SSi. The cells were co-transplanted with CD45.2+ BM cells into lethally (11 Gy) irradiated CD45.2+ recipient mice. (B) Donor chimerism 8 months after transplantation was used to determine LT-HSC capacity in the BM and spleen. Statistical significance was determined using the Log-rank (Mantel-Cox) test (* <0.05; ** <0.01).
Mentions: To determine whether SSi interferes with the capacity of X-RARα to maintain long-term stem cell (LT-HSC) capacity, we performed a CRA assay [38] on PML/RARα-positive Sca1+/lin− HPCs cultured for seven days in the presence/absence of 40 µM SSi (Figure 7A). The population density of LT-HSC was assessed via CD45.1/CD45.2 chimerism, which demonstrates the capacity of the PML/RARα-positive CD45.1+ donor cells to compete the reconstitution of hematopoiesis by CD45.2+ BM cells in lethally irradiated CD45.2+ recipients (Figure 7A). Upon exposure to SSi, we found that after 8 months, the proportion of PML/RARα-positive HPCs was significantly reduced in the BM and spleens of recipient mice compared with untreated controls (Figure 7B).

Bottom Line: 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.Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling.We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Goethe-University, Frankfurt, Germany.

ABSTRACT
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 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-RARα-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 β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, 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.

Show MeSH
Related in: MedlinePlus