LYMPHOID NEOPLASIA Adhesion to osteopontin in the bone marrow niche regulates lymphoblastic leukemia cell dormancy

Acute lymphoblastic leukemia (ALL) in adults initially responds well to induction chemotherapy, with greater than 80% of patients attaining a complete remission (CR). Unfortunately, most initial CRs are short lived, and overall survival rate is only 30% to 40% for adults who are diagnosed before age 60 years. Although outcomes in the pediatric population are better, a significant number of patients still experience relapsed or refractory disease. Relapses in both populations are believed to be the outgrowth of minimal residual disease (MRD) that is not completely eliminated by chemotherapy. Indeed, it has been demonstrated that patients with the lowest levels of detectable MRD at CR have the best prognosis and least likelihood of relapse. Strategies to overcome resistance and reduce MRD may therefore have the potential to increase overall survival duration. Antiapoptotic signals from the host tissue microenvironment are increasingly recognized as important mechanisms of malignant cell survival against chemotherapy. Our previous work using the Nalm-6 model of ALL has shown that the bone marrow (BM) microenvironment plays a critical role in disease spread and in the dysregulation of normal hematopoiesis that occurs during leukemic growth. To metastasize and outcompete native BM cells, leukemic cells co-opt normal signaling mechanisms within hematopoietic stem cell (HSC) niches. At least 2 distinct HSC niches, one perivascular and one endosteal (or bony), exist in the BM. In the basal state, interactions between HSCs and specific cells and molecules within these niches modulate HSC transit and self-renewal. Although the anatomic and molecular distinctions between these niches are controversial, evidence suggests that the endosteal niche maintains a population of quiescent HSCs with high reconstitution potential, whereas the perivascular niche harbors more activated HSCs. Stromal cell-derived factors, including cytokines and extracellular matrix proteins (ECMs), play a significant role in niche regulation of the benign HSC population. One important protein expressed by endosteal osteoblasts and implicated in HSC migration and self-renewal is osteopontin (OPN). Extracellular OPN is a multidomain-secreted glycoprotein that can function as a soluble cytokine or chemokine as well as an adhesive component of the ECM. It is bound by multiple cell surface receptors including CD44, aVb3, (a4, a9, a5)b1, and a4b7 integrins. 15-18 OPN expression is necessary for proper trans-marrow migration and lodgment of HSCs at the endosteal surface, a process mediated by a4b1 and a9b1 integrins. Furthermore, HSC engagement with OPN constrains HSC pool size, and there is an increased number of cycling progenitors in the marrow and peripheral blood of OPN mice. The role of OPN has been extensively investigated in solid malignancies, with multiple studies showing that OPN positively regulates tumor cell proliferation and metastasis. Despite the well-defined functions for OPN in solid tumor and benign HSC biology, scarce data exist regarding OPN and leukemia. A limited number of studies of patients with acute myeloid leukemia (AML) demonstrate that increased BM transcript and serum