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Acute Non-Lymphocytic Leukemias

Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein

Abstract

Secreted protein, acidic and rich in cysteine (SPARC), is a matricellular glycoprotein with growth-inhibitory and antiangiogenic functions. Although SPARC has been implicated as a tumor suppressor in humans, its function in normal or malignant hematopoiesis has not previously been studied. We found that the leukemic cells of AML patients with MLL gene rearrangements express low to undetectable amounts of SPARC whereas normal hematopoietic progenitors and most AML patients express this gene. SPARC RNA and protein levels were also low or undetectable in AML cell lines with MLL translocations. Consistent with its tumor suppressive effects in various solid tumor models, exogenous SPARC protein selectively reduced the growth of cell lines with MLL rearrangements by inhibiting cell cycle progression from G1 to S phase. The lack of SPARC expression in MLL-rearranged cell lines was associated with dense promoter methylation. However, we found no evidence of methylation-based silencing of SPARC in primary patient samples. Our results suggest that low or absent SPARC expression is a consistent feature of AML cells with MLL rearrangements and that SPARC may function as a tumor suppressor in this subset of patients. A potential role of exogenous SPARC in the therapy of MLL-rearranged AML warrants further investigation.

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Acknowledgements

This work was supported by National Institutes of Health Grants K08 CA818818 (JFD), R01 CA90916 (GVD and BIS), R01 CA 92474 (BIS) and M01 RR 00070 (General Clinical Research Center, Stanford University School of Medicine; NJL), Cincinnati Children's Hospital Research Foundation Trustee Award (LL) and by the American Lebanese Syrian Associated Charities (ALSAC) and by the Cancer Center Support Grant CA21765 from the National Cancer Institute (SCR).

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Correspondence to J F DiMartino.

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DiMartino, J., Lacayo, N., Varadi, M. et al. Low or absent SPARC expression in acute myeloid leukemia with MLL rearrangements is associated with sensitivity to growth inhibition by exogenous SPARC protein. Leukemia 20, 426–432 (2006). https://doi.org/10.1038/sj.leu.2404102

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