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// Carmine Selleri 1, * , Nunzia Montuori 2, * , Annamaria Salvati 3 , Bianca Serio 1 , Ada Pesapane 2 , Patrizia Ricci 1 , Anna Gorrasi 3 , Anna Li Santi 3 , Gunilla Hoyer-Hansen 4 , Pia Ragno 3 1 Department of Medicine and Surgery, University of Salerno, Salerno, Italy 2 Department of Translational Medical Sciences, “Federico II” University, Naples, Italy 3 Department of Chemistry and Biology, University of Salerno, Salerno, Italy 4 The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark * These authors have contributed equally to this work Correspondence to: Pia Ragno, email: pragno@unisa.it Keywords: urokinase receptor, uPAR, hematopoietic stem cells, bone marrow microenvironment, leukemia Received: January 04, 2016 Accepted: July 18, 2016 Published: August 08, 2016 ABSTRACT Hematopoietic stem cells (HSCs) reside in bone marrow (BM) and can be induced to mobilize into the circulation for transplantation. Homing and lodgement into BM of transplanted HSCs are the first critical steps in their engraftment and involve multiple interactions between HSCs and the BM microenvironment. uPAR is a three domain receptor (DIDIIDIII) which binds urokinase, vitronectin, integrins. uPAR can be cleaved and shed from the cell surface generating full-length and cleaved soluble forms (suPAR and DIIDIII-suPAR). DIIDIII-suPAR can bind fMLF receptors through the SRSRY sequence (residues 88-92). We previously reported the involvement of soluble uPAR in HSC mobilization. We now investigate its possible role in HSC homing and engraftment. We show similar levels of circulating full-length suPAR in healthy donors and in acute myeloid leukemia (AML) patients before and after the pre-transplant conditioning regimen. By contrast, levels of circulating DIIDIII-suPAR in AML patients are higher as compared to controls and significantly decrease after the conditioning. We found that suPAR and uPAR 84-95 , a uPAR-derived peptide which mimics active DIIDIII-suPAR, induce a significant increase in Long Term Culture (LTC)-Initiating Cells (ICs) and in the release of clonogenic progenitors from LTCs of CD34 + HSCs. Further, suPAR increases adhesion and survival of CD34 + KG1 AML cells, whereas uPAR 84-95 increases their proliferation. Thus, circulating DIIDIII-suPAR, strongly increased in HSC mobilization, is indeed down-regulated by pre-transplant conditioning, probably to favour HSC homing. BM full-length suPAR and DIIDIII-suPAR may be involved in HSC lodgement within the BM by contributing to a suitable microenvironment.

The 67 kDa laminin receptor (67LR) is a non-integrin cell surface receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potentialin many human solid tumors, recommending this receptor as a new promising target for cancer therapy. This is supported by in vivo studies showing that 67LR downregulation reduces tumour cell proliferation and tumour formation by inducing apoptosis. 67LR association with the anti-apoptotic protein PED/PEA-15 activates a signal transduction pathway, leading to cell proliferation and resistance to apoptosis. However, the main function of 67LR is to enhance tumor cell adhesion to the LM of basement membranes and cell migration, two crucial events in the metastasis cascade. Thus, inhibition of 67LR binding to LM has been proved to be a feasible approach to block metastatic cancer cell spread. Despite accumulating evidences on 67LR overexpression in hematologic malignancies, 67LR role in these diseases has not been clearly defined. Here, we review 67LR expression and function in normal and malignant hematopoietic cells, 67LR role and prognostic impact in hematological malignancies and first attempts in targeting its activity.

Although osteoporosis is a relatively common complication after allogeneic stem cell transplantation, the role of bisphosphonates in its management has not yet been completely established. Thirty-two patients who underwent allogeneic stem cell transplantation were prospectively evaluated for bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) after a median period of 12.2 months. Then, 15 of the patients with osteoporosis or rapidly progressing osteopenia (bone loss > 5%/yr) received three monthly doses of 4 mg zoledronic acid iv. Fifteen patients were followed up without treatment, and all 30 patients were reevaluated after 12 months for BMD and bone turnover markers. By using enriched mesenchymal stem cells in the colony-forming units fibroblast (CFU-F) assay, we evaluated the osteogenic stromal lineage. This procedure was performed in both groups of patients at study entry and after 12 months. The average BMD loss was 3.42% at LS and 3.8% at FN during a 1-yr longitudinal evaluation in 32 patients. Subsequently, BMD increased at both LS and FN (9.8 and 6.4%, respectively) in the zoledronic acid-treated cohort. Hydroxyproline excretion decreased, and serum bone-specific alkaline phosphatase increased significantly, whereas serum osteocalcin increase did not reach the limit of significance. A significant increase in CFU-F growth in vitro was induced by in vivo zoledronic acid administration. In the untreated group, no significant change was observed in bone turnover markers, LS BMD (–2.1%), FN BMD (–2.3%), and CFU-F colony number. In conclusion, short-term zoledronic acid treatment consistently improved both LS and FN BMD in transplanted patients who were at high risk for fast and/or persistent bone loss, partly by increasing the osteogenic progenitors in the stromal cell compartment.

Two patients with acute promyelocytic leukemia (APL) relapsed at 111 and 84 months after achievement of complete remission (CR) induced by a combination of all- trans retinoic acid and chemotherapy. In both patients molecular remission, obtained after consolidation, had been confirmed at 60 months from CR achievement. At relapse, morphological, immunophenotypic, cytogenetic, and molecular analyses showed findings identical to those at diagnosis. Hematological and molecular remission was induced with the identical treatment applied at diagnosis. We conclude that, although infrequently, patients with APL treated with modern combination therapy can experience very late relapse and can be rescued with treatment similar to that administered at diagnosis.