RIPK3 Induces Leukemia-Initiating Cell Death and Differentiation

Acute myeloid leukemia (AML) is sustained by a subpopulation of leukemia-initiating cells (LIC) with disrupted myeloid progenitor commitment and differentiation, and the persistence of these cells after treatment presents a major clinical challenge. Mature myeloid cells often undergo receptor-interacting protein kinase 3 (RIPK3)–dependent cell death, which is accompanied by inflammation and the release of cytokines from dying cells; however, the role of RIPK3-dependent cell death in AML has not been fully elucidated. Höckendorf, Yabal, and colleagues explored the role of RIPK3 in leukemogenesis using a mouse model of FLT3-ITD–driven myeloproliferative neoplasia (MPN), in which FLT3-ITD–transduced Ripk3^−/− or Ripk3-wild-type bone marrow was transplanted into lethally irradiated mice. Mice transplanted with Ripk3^−/− bone marrow developed MPN more quickly than those transplanted with wild-type bone marrow, and exhibited greater leukemic cell infiltration. Ripk3 deletion rendered FLT3-ITD splenocytes serially transplantable, indicating an enhanced ability of transformed hematopoietic stem and progenitor cells (HSPC) to survive and propagate. Moreover, Ripk3 deletion resulted in a shift toward more primitive myeloid progenitors in the HSPC compartment, suggesting that RIPK3 promotes myeloid progenitor cell differentiation. Further, RIPK3 induced cell death mediated by TNFR, preventing LIC accumulation. FLT3-ITD signaling promoted myeloid differentiation via induction of RIPK3-dependent cytokine release, and In vivo, Ripk3 loss reversed LIC accumulation and leukemogenesis. Consistent with a broader role for suppression of RIPK3-induced LIC cell death and differentiation in AML, RIPK3 expression was reduced in patients with several subtypes of AML, and Ripk3 deletion also accelerated leukemogenesis in a mouse model of AML-ETO–driven leukemia. However, these findings did not extend to MLL-translocated AML, which does not exhibit reduced RIPK3 expression. The finding that RIPK3 promotes inflammatory cytokine–mediated death and differentiation of LICs supports a role for RIPK3 as an AML tumor suppressor, and suggests reactivation of RIPK3 as a potential therapeutic approach in some AML subtypes.

Höckendorf U, Yabal M, Herold T, Munkhbaatar E, Rott S, Jilg S, et al. RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells. Cancer Cell 2016;30:75–91.