Abstract

BackgroundCD274 (programmed death ligand 1, also known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Increasing evidence indicates that functional monoclonal antibodies of CD274 may potently enhance the antitumor effect in many cancers. However, the role of CD274 in leukemia-initiating cells (LICs) remains largely unknown.MethodsWe established an MLL-AF9-induced acute myeloid leukemia (AML) model with wild-type (WT) and CD274-null mice to elucidate the role of CD274 in the cell fates of LICs, including self-renewal, differentiation, cell cycle, and apoptosis. RNA sequencing was performed to reveal the potential downstream targets, the results of which were further validated both in vitro and in vivo.ResultsIn silico analysis indicated that CD274 level was inversely correlated with the overall survival of AML patients. In Mac-1+/c-Kit+ mouse LICs, CD274 was expressed at a much higher level than in the normal hematopoietic stem cells (HSCs). The survival of the mice with CD274-null leukemia cells was dramatically extended during the serial transplantation compared with that of their WT counterparts. CD274 deletion led to a significant decrease in LIC frequency and arrest in the G1 phase of the cell cycle. Interestingly, CD274 is not required for the maintenance of HSC pool as shown in our previous study. Mechanistically, we demonstrated that the levels of both phospho-JNK and Cyclin D2 were strikingly downregulated in CD274-null LICs. The overexpression of Cyclin D2 fully rescued the loss of function of CD274. Moreover, CD274 was directly associated with JNK and enhanced the downstream signaling to increase the Cyclin D2 level, promoting leukemia development.ConclusionsThe surface immune molecule CD274 plays a critical role in the proliferation of LICs. The CD274/JNK/Cyclin D2 pathway promotes the cell cycle entry of LICs, which may serve as a novel therapeutic target for the treatment of leukemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0350-6) contains supplementary material, which is available to authorized users.

Highlights

  • CD274 is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1)

  • CD274 is highly expressed on leukemia-initiating cells (LICs) and promotes Acute myeloid leukemia (AML) development To explore the role of CD274 in leukemogenesis, we first examined the expression of CD274 in phenotypic Mac-1+/c-Kit+ LICs and different cell population of normal bone marrow hematopoietic cells by quantitative RT-PCR

  • The RNA-sequencing results indicated that CD274 might be involved in the AML development through the cell cycle regulation. To confirm whether these cell cycle-related genes were potential downstream targets of CD274, we examined their expressions in WT and CD274-null LICs by quantitative RT-PCR and revealed that the levels of both p21 and p16 were increased, whereas those of Cyclin D2 and CDK6 were decreased in CD274-null LICs compared to WT ones (Fig. 3c)

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Summary

Introduction

CD274 (programmed death ligand 1, known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Similar surface immune ligands and receptors, such as CD47, interleukin-3 receptor, and CD97, have been revealed to play critical roles in the stemness maintenance or immune escape in both solid caners and malignant hematopoietic diseases [8,9,10,11]. Targeting such surface immune molecules with either monoclonal antibodies or engineered chimeric antigen receptor T cells (CAR T) may be the most promising and powerful strategy to eliminate LICs and other types of cancer stem cells [12,13,14]

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