抑制TNF/IL1-RIP1/RIP3-calpain信号促进ATRA和IFN对AML的诱导分化治疗

Acute myeloid leukemia (AML) is the most common type of leukemia. Current treatment for AML patients is still an anthracycline antitumor antibiotic plus ARA-C (3+7) chemotherapy which induces complete remission in 50-80% AML patients; however most patients die of disease relapse and drug resistance. The cure of such disease is still impossible in most patients especially in patients >65 years old. Thus, development of more effective and low toxic novel treatment for AML is urgent. .All trans-retinoic acid (ATRA)-induced differentiation has been approved to be the most effective and low toxic therapy for acute premyelocytic leukemia (APL), M3 sub-type of AML. However, such treatment is not effective in other sub-types of AML patients. We found that many non-APL AML cells secret inflammatory cytokines such as TNF. Such cytokines stimulate the activation of RIP1 and RIP3 which in turn represses calpain-2-mediated cleavage of STAT3a, MYC and SOCS1. Such signaling is required for maintaining the undifferentiated state of leukemia cells. Inhibition of RIP1 or RIP3 in AML cells induces partial differentiation and sensitizes AML cells to ATRA and INF (interferon-r) –induced differentiation. Our study suggests that RIP1/RIP3 inhibition plus ATRA or IFN might provide a better treatment for AML by induced differentiation. We demonstrated that TNF-RIP1/RIP3 signaling represses AML differentiation by repressing calpain 2-mediated cleavage of key self-renewal/proliferation factors, including STAT3a, MYC and SOCS1. We want to evaluate whether inhibition of RIP1/RIP3 can facilitate ATRA/IFN-induced differentiation in human AML cells in xenograft model. We also try to use genetic mutated murine AML cells to further dissect TNF-RIP1/RIP3-calpain pathway in ATRA/IFN induced differentiation. By such study, we expect to provide using information for clinical translation of inhibition of RIP1/RIP3 signaling for AML treatment when combined with ATRA or IFN. We also expect to elucidate the upstream stimulators and downstream mediators of RIP1/RIP3 pathway in pathogenesis of AML and ATRA and IFN-induced differentiation.

诱导分化是治疗白血病的低毒且有效手段，但这种治疗目前只限于急性早幼粒细胞白血病。我们研究表明，大多数急性粒细胞白血病（AML）细胞分泌高水平TNF和IL1。TNF/IL1通过诱导RIP1/RIP3信号而抑制calpain2介导的STAT3、MYC和SOCS1的切割而抑制AML细胞的分化。抑制TNF/IL1-RIP1/RIP3信号或诱导Calpain2的活化均可引起AML细胞中STAT3、MYC和SOCS1的切割，从而导致AML细胞的部分分化和促进ATRA或IFN的诱导分化。我们将研究是否可以通过：1）抑制RIP1和RIP3， 2）激活calpain，3） 诱导STAT3、MYC或SOCS1的切割等策略，来促进ATRA和IFN对人AML的诱导分化治疗。我们将研究RIP/RIP3信号调节calpain2切割STAT3、MYC或SOCS1的分子机制。本研究将为诱导分化治疗AML提供新型的思路。

本课题中我们研究了通过：1 ）抑制RIP1和RIP3，2）激活calpain，3）诱导STAT3、MYC或SOCS1的切割等策略，来促进ATRA和IFN对人AML的诱导分化治疗。我们研究了通过RIP/RIP3信号调节calpain2，切割STAT3、MYC或SOCS1的分子机制。我们发现，TNF/IL1通过诱 导RIP1/RIP3信号而抑制calpain2介导的STAT3、MYC和SOCS1的切割而抑制AML细胞的分化。在体内或体外抑制TNF/IL1-RIP1/RIP3信号或诱导Calpain2的活化均可引起AML细胞中STAT3、MYC和SOCS1的切割，从而导致AML细胞的部分分化和促进ATRA或IFN的诱导分化。通过诱导白血病细胞的分化，实现低毒有效的治疗白血病的方法。