UC Berkeley

Leptomeningeal dissemination (LMD) is frequently observed in patients with B-cell acute lymphoblastic leukemia (B-ALL), particularly those that carry the Philadelphia chromosome (Ph+). To prevent disease relapse from B-ALL cells in the meninges, patients are treated prophylactically with intrathecal chemotherapy, which is often accompanied by deleterious side effects such as neuropathy. Using a mouse model of B-ALL that recapitulates the genetic lesions commonly found in Ph+ B-ALL (expression of Ph and loss of tumor suppressor Arf), I characterized the molecular and cellular defects during meningeal dissemination, and explored the underlying mechanism through which B-ALL cells promote meningeal dissemination. In this Ph+ B-ALL model, meningeal dissemination was found in conjunction with extensive osteoclast-mediated osteolysis in the skull, caused by the expansion and activation of osteoclasts. Repression of osteoclast differentiation and activation in the Ph+ B-ALL model, either by RANK-Fc or bisphosphonate treatment, significantly delayed the onset of meningeal dissemination, suggesting the osteolysis of the skull provides a favorable stromal environment for meningeal tumor growth. I also found that the Ph+ B-ALL tumors exhibited a high level of Rankl and Tnfα, at least in part, through aberrant STAT5A signaling downstream of inappropriate activation of the ABL kinase component of the BCR-ABL fusion protein. Rankl and Tnfα both promote osteoclast differentiation and osteolysis, and hence, early colonization and expansion of Ph+ B-ALL cells in the meninges. Taken together, my studies reveal an unexpected connection between meningeal dissemination and osteolysis, and will likely provide important insights into patient stratification and LMD prevention in human B-ALL patients.