Hedgehog Pathway Activation Promotes Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is frequently characterized by internal tandem duplication (ITD) mutations in FMS-related tyrosine kinase 3 (FLT3), which lead to constitutive FLT3 activation and are associated with poor prognosis. However, FLT3-ITD expression alone is not sufficient to induce AML in mouse models, and the clinical efficacy of FLT3 inhibitors has been limited, underscoring the importance of identifying cooperating genetic events. Lim and colleagues found that expression of GLI2, which encodes a Hedgehog pathway effector, was specifically increased in FLT3-ITD⁺ AML data sets and primary FLT3-ITD⁺ patient samples and that elevated GLI2 expression in FLT3-ITD⁺ AML correlated with reduced overall survival, suggesting a role for Hedgehog signaling in this AML subgroup. Consistent with this idea, constitutive activation of the Hedgehog pathway via expression of mutant Smoothened (SmoM2) in transgenic mice expressing FLT3-ITD induced the progression of indolent myeloproliferative neoplasms to infiltrative myeloid leukemia and resulted in significantly shorter survival compared with heterozygous FLT3-ITD mice. Mechanistically, Hedgehog signaling augmented the proliferation of granulocyte/monocyte progenitors in the bone marrow of FLT3-ITD;SmoM2 mice via increased activation of STAT5, a downstream target of FLT3-ITD implicated in the survival and proliferation of AML cells. Dual treatment with the Hedgehog pathway inhibitor IPI-926 and the FLT3 antagonist sorafenib more effectively suppressed STAT5 activity in human FLT3-ITD⁺ AML cell lines compared with single-agent treatment, resulting in enhanced inhibition of leukemic growth in vitro. Furthermore, combined treatment of FLT3-ITD;SmoM2 mice with sorafenib and IPI-926 significantly reduced leukemic cells in the peripheral blood and bone marrow, decreased splenomegaly, and prolonged survival compared with either agent alone. These results demonstrate that aberrant Hedgehog pathway signaling can cooperate with FLT3-ITD mutations to drive AML and suggest a therapeutic strategy to increase the efficacy of FLT3 inhibitors in FLT3-ITD⁺ AML.

Lim Y, Gondek L, Li L, Wang Q, Ma H, Chang E, et al. Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. Sci Transl Med 2015;7:291ra96.