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Haematologica 2020 Volume 105(1):136-147
Chronic Myeloid Leukemia
The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1 - CD44 axis
Parimala Sonika Godavarthy,1 Rahul Kumar,1 Stefanie C. Herkt,2 Raquel S. Pereira,1 Nina Hayduk,1 Eva S. Weissenberger,1 Djamel Aggoune,1 Yosif Manavski,3 Tina Lucas,3 Kuan-Ting Pan,4 Jenna M. Voutsinas,5 Qian Wu,5 Martin C. Müller,6 Susanne Saussele,7 Thomas Oellerich,8,9 Vivian G. Oehler,10 Joern Lausen2 and Daniela S. Krause1,9,11,12
1Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany; 2Institute for Transfusion Medicine DRK- Blutspendedienst Baden- Württemberg – Hessen, Frankfurt am Main, Germany; 3Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany; 4Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany; 5Fred Hutchinson Cancer Research Center, Clinical Research Division, Biostatistics, Seattle, WA, USA; 6Institute for Hematology and Oncology, Mannheim, Germany; 7Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany; 8Department of Internal Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany; 9German Cancer Research Center and German Cancer Consortium, Heidelberg, Germany; 10Fred Hutchinson Cancer Research Center, Clinical Research Division, Division of Hematology, University of Washington Medical Center, Seattle, WA, USA; 11Faculty of Medicine, Johann Wolfgang Goethe University, Frankfurt and 12Frankfurt Cancer Institute, Frankfurt, Germany
ABSTRACT
The endosteal bone marrow niche and vascular endothelial cells pro- vide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone mar- row endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E- selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1+ cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic tran- scription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrin- sic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules – which could be exploited therapeuti- cally in the future.
Introduction
The bone marrow (BM) microenvironment and in particular the endosteal BM niche,1 vascular endothelial cells,2 as well as secreted factors and mesenchymal stro- mal cells,3,4 protect leukemic stem cells (LSC) from eradication by various therapies, thereby leading to treatment resistance, disease relapse and disease progression. E- selectin, an adhesion molecule exclusively expressed on endothelial cells and acti- vated by cytokines, is an essential component of the vascular niche in the BM microenvironment, where it promotes the proliferation of normal hematopoietic stem cells (HSC).5 E-selectin6 and one of its ligands,7 CD44,8 have been shown to be
Correspondence:
DANIELA S. KRAUSE
krause@gsh.uni-frankfurt.de
Received: November 26, 2018. Accepted: April 23, 2019. Pre-published: April 24, 2019.
doi:10.3324/haematol.2018.212365
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