AML patients with myeloid sarcoma (MS) usually had a poor outcome. Our clinical data revealed that AML patients harboring MLL/AF10 and RAS gene mutations were associated with MS formation. By using retroviral transduction/transplantation assay, we demonstrated that the mice transplanted with bone marrow (BM) cells carrying cooperating MLL/AF10(OM-LZ) and KRAS-G12C mutations induced MPD-like myeloid leukemia and MS. Gene expression analyses identified Gpr125, an adhesion G protein-coupled receptor, was up-regulated in the cells carrying cooperating mutations than the cells carrying MLL/AF10(OM-LZ) alone. Knockdown of Gpr125 by RNA interference reduced the number and the size of MS, suggesting that Gpr125 was involved in the MS formation. As Gpr125 contains a HormR domain with Lysine-Glycine-Aspartic acid (KGD) motif which is known to involve in the cell-extracellular matrix (ECM) and cell-cell adhesion, we investigated whether a cyclic RGD peptide drug, eptifibatide (Ep), could interfere MS formation. An in vitro cell-ECM binding assay showed that Gpr125 interacted with fibronectin. Ep reduced leukemia cell-fibronectin binding. Ep also reduced homotypic leukemia cell adhesion and leukemia cell-adipocyte adhesion. In vivo assay demonstrated that Ep reduced leukemia cells recruitment to the adipose tissues, spleen and bone marrow. Our results suggested that blocking Gpr125-mediated cell-ECM and cell-cell adhesion might be helpful to interfere MS formation and BM/spleen recruitment of leukemia cells.
Off Label Use: Eptifibatide (Integrilin, Millennium Pharmaceuticals, also co-promoted by Schering-Plough/Essex), is an antiplatelet drug of the glycoprotein IIb/IIIa inhibitor class.
Author notes
Asterisk with author names denotes non-ASH members.
