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Acute Myeloid Leukemia
Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival
Steven M. Kornblau,1* Peter P. Ruvolo,1* Rui-Yu Wang,1 V. Lokesh Battula,1 Elizabeth J. Shpall,2 Vivian R. Ruvolo,1 Teresa McQueen,1 YiHua Qui,1
Zhihong Zeng,1 Sherry Pierce,1 Rodrigo Jacamo,1 Suk-Young Yoo,3
Phuong M. Le,1 Jeffrey Sun,1 Numsen Hail Jr,1 Marina Konopleva1 and Michael Andreeff1
1Section of Molecular Hematology and Therapy, Department of Leukemia; 2Department of Stem Cell Transplantation and 3Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, TX, USA
ABSTRACT
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 signifi- cantly 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 expres- sion defined four MSC protein expression signatures: Class 1, Class 2, Class 3, and Class 4. These cell populations appear to have clinical rele- vance. 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/refrac- tory) 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 over- expressed p53/p21 axis as confirmed by high β-galactosidase staining. In addition, overexpression of BCL-XL in leukemia MSC might give sur- vival advantage under conditions of senescence or stress and over- expressed 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.
Introduction
There is growing evidence to support the importance of the leukemia bone mar- row (BM) niche in the process of acute myeloid leukemia (AML) chemoresis- tance.1,2 Hence, optimal therapeutic strategies should also address neighboring cells in the tumor microenvironment. The critical support cells in the leukemia BM microenvironment are mesenchymal stromal cells (MSC).3-8 Depending on the type, MSC can act either to support or suppress tumors.4,8-15 Our group and others have found that MSC support leukemia cell survival by diverse mechanisms that include secretion of cytokines and chemokines, activation of survival signaling in tumor cells, and blocking immune surveillance by suppressing natural killer (NK) and T cells.2-5,13
Mesenchymal stromal cells are essential for human hematopoiesis, particularly as a source of SDF-1, which regulates homing, proliferation, and differentia- tion.6,9,10,16-18 Moreover, studies from our group and others have demonstrated that MSC protect leukemia cells from chemotherapy.6,19-23 We have recently found that there is reciprocal activation of NFkB signaling between MSC and AML and acute lymphoblastic leukemia (ALL) cells that likely contribute to the effectiveness of the microenvironment to protect malignant cells.7 Medyouf et al. recently demonstrat-
Haematologica 2018 Volume 103(5):810-821
*SMK and PPR contributed equally to this work.
Correspondence:
skornblau@mdanderson.org or mandreef@mdanderson.org
Received: May 9, 2017. Accepted: February 1, 2018. Pre-published: March 15, 2018.
doi:10.3324/haematol.2017.172429
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/810
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