title: 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.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA. jorge.dimartino@cchmc.org
authors.forename: J F
authors.initials: JF
authors.lastname: DiMartino
authors.forename: N J
authors.initials: NJ
authors.lastname: Lacayo
authors.forename: M
authors.initials: M
authors.lastname: Varadi
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Saraiya
authors.forename: Y
authors.initials: Y
authors.lastname: Ravindranath
authors.forename: R
authors.initials: R
authors.lastname: Yu
authors.forename: B I
authors.initials: BI
authors.lastname: Sikic
authors.forename: S C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: G V
authors.initials: GV
authors.lastname: Dahl
mesh_terms: D000208:Acute Disease; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; C497422:KMT2A protein, human; D015676:Osteonectin; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase