Haematologica (May 2018)

Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival

  • Steven M. Kornblau,
  • Peter P. Ruvolo,
  • Rui-Yu Wang,
  • V. Lokesh Battula,
  • Elizabeth J. Shpall,
  • Vivian R. Ruvolo,
  • Teresa McQueen,
  • YiHua Qui,
  • Zhihong Zeng,
  • Sherry Pierce,
  • Rodrigo Jacamo,
  • Suk-Young Yoo,
  • Phuong M. Le,
  • Jeffrey Sun,
  • Numsen Hail,
  • Marina Konopleva,
  • Michael Andreeff

DOI
https://doi.org/10.3324/haematol.2017.172429
Journal volume & issue
Vol. 103, no. 5

Abstract

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Mesenchymal stromal cells (MSC) support acute myeloid leukemia (AML) cell survival in the bone marrow (BM) microenvironment. Protein expression profiles of AML-derived MSC are unknown. Reverse phase protein array analysis was performed to compare expression of 151 proteins from AML-MSC (n=106) with MSC from healthy donors (n=71). Protein expression differed significantly between the two groups with 19 proteins over-expressed in leukemia stromal cells and 9 over-expressed in normal stromal cells. Unbiased hierarchical clustering analysis of the samples using these 28 proteins revealed three protein constellations whose variation in expression defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical relevance. Specifically, patients with Class 3 cells have longer survival and remission duration compared to other groups. Comparison of leukemia MSC at first diagnosis with those obtained at salvage (i.e. relapse/refractory) showed differential expression of 9 proteins reflecting a shift toward osteogenic differentiation. Leukemia MSC are more senescent compared to their normal counterparts, possibly due to the overexpressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, overexpression of BCL-XL in leukemia MSC might give survival advantage under conditions of senescence or stress and overexpressed galectin-3 exerts profound immunosuppression. Together, our findings suggest that the identification of specific populations of MSC in AML patients may be an important determinant of therapeutic response.