Leukemia stem cells (LSCs) requires frequent adaptation to maintenance self-renewal ability despite they are longer exposure to cell-intrinsic and cell-extrinsic stresses. However, the mechanism by which LSCs maintain their leukemogenic activities and how individual LSCs respond to stress remain poorly understood. Herein, we found that DNAJC10, a member of HSP40 family, was frequently upregulated in various types of acute myeloid leukemia (AML) and in LSC-enriched cells. Deficiency of DNAJC10 leads to a dramatic increase in the apoptosis of both human leukemia cell lines and LSCs enriched populations. Although DNAJC10 is not required for normal hematopoiesis, deficiency of Dnajc10 significantly abrogated AML development and suppressed self-renewal of LSCs in the MLL-AF9–induced murine leukemia model. Mechanistically, inhibition of DNAJC10 specifically induces endoplasmic reticulum (ER) stress and promotes activating of PERK-EIF2α-ATF4 branch of unfolded protein response (UPR). Blocking PERK by GSK2606414 (PERKi) or shRNA rescued the loss of function of DNAJC10 both in vitro and in vivo. Importantly, deficiency of DNAJC10 increased sensitivity of AML cells to daunorubicin (DNR) and cytarabine (Ara-C). These data revealed that DNAJC10 functions as an oncogene in MLL-AF9-induced AML via regulating PERK branch of the UPR. DNAJC10 may be an ideal therapeutic target for eliminating LSCs and improving the effectiveness of DNR and Ara-C.
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