Identification of Syndecan-1 As a Key Dependency of Myeloid Leukemia Growth and Dissemination

Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus identifying the cells responsible for residual disease and leukemia re-growth is critical to better understand how they are regulated. Here we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of therapy resistant leukemia propagating cells in aggressive myeloid malignancies, and provides a new strategy for defining their core dependencies. Specifically, we carried out a high throughput screen using Msi2 reporter blast crisis chronic myeloid leukemia (bcCML) and identified syndecan-1 (Sdc1), a cell surface proteoglycan, as preferentially expressed in therapy resistant bcCML cells, and critical for bcCML function. Specifically, in Sdc1^-/- mice, Sdc1 loss led to a defect in bcCML growth and propagation in vitro and in vivo, and markedly improved survival. Further, live imaging revealed that Sdc1 loss had a striking impact on the spatiotemporal dynamics of leukemia cells, impairing their localization, migration and systemic dissemination. Mechanistically, distinct elements of Sdc1 contributed to leukemia growth and dissemination, with the core protein alone being able to rescue the growth defect, but the heparin sulfate chains that mediate matrix attachment being needed for migration. These data present a new platform for delineating the biological underpinnings of leukemia stem cell function, and identify Sdc1 as a central regulator of leukemia stem cell growth and dissemination.