JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling

Zhang, Yaping; Xia, Fangzhen; Liu, Xiaoye; Yu, Zhuang; Xie, Li; Liu, Ligen; Chen, Chiqi; Jiang, Huimin; Hao, Xiaoxin; He, Xiaomin; Zhang, Feifei; Gu, Hao; Zhu, Jun; Bai, Hao; Zhang, Cheng Cheng; Chen, Guoqiang; Zheng, Junke

doi:10.1172/jci93198

Cited by 47 publications

(34 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, it may well be that JAM-C expression by leukemic subsets plays a role in drug resistance, irrespective of the maturation compartment of leukemic cells. This would be in agreement with a cell autonomous function of JAM-C in leukemic cells as reported recently (6). Indeed, JAM-C has been shown to associate in cis with LRP5 and to signal through AKT/b-catenin/CCND1 axis to maintain leukemic cell self-renewal.…”

supporting

confidence: 92%

JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Response

Grandis¹,

Mancini²,

Vey³

et al. 2018

Cancer Research

View full text Add to dashboard Cite

supporting

confidence: 92%

JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Response

Grandis¹,

Mancini²,

Vey³

et al. 2018

Cancer Research

View full text Add to dashboard Cite

“…β-catenin has been demonstrated as a critical regulator of the self-renewal and therapeutic target for various cancer stem cells including leukemia-initiating cells (LICs) (12,13). Casein kinase 1α (CK1α), encoded by CSNK1A1, is a classical negative regulator for the Wnt/β-catenin signaling pathway (14).…”

Section: Introductionmentioning

confidence: 99%

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

Huang

Gan

et al. 2020

Oncol Rep

View full text Add to dashboard Cite

Enhancement of autophagy serves as a promising therapeutic strategy for cancer, including acute myeloid leukemia (AML). Casein kinase 1α (CK1α), encoded by CSNK1A1, regulates Wnt/β-catenin, p53 and other key signaling pathways, and is critically involved in tumor progression. However, the relationship and mechanism of CK1α with autophagy in AML still remain unclear. In the present study, it was found that AML patients had higher expression of CSNK1A1 mRNA than healthy donors. Furthermore, we analyzed 163 cases of AML patients in the LAML database of TCGA and found that AML patients with high CSNK1A1 had shorter overall survival than those with low or medium CSNK1A1 expression. Furthermore, we demonstrated that CK1α was a negative regulator of autophagy and apoptosis. Pharmacologic inhibition of CK1α using D4476 or CK1α knockdown via lentivirus-mediated shRNA suppressed proliferation and the clone formation by enhancing autophagic flux and apoptosis in AML cell lines as well as in patient blast cells. Intriguingly, D4476-induced cell death was aggravated in combination with an autophagy inhibitor, Spautin-1, suggesting that autophagy may be a pro-survival signaling. CK1α interacted with murine double minute 2 (MDM2) and p53, and CK1α inhibitor D4476 significantly upregulated p53 and phosphorylated 5' AMP-activated protein kinase (AMPK), and substantially inhibited the phosphorylation of mammalian target of rapamycin (mTOR). Our findings indicate that CK1α promotes AML by suppressing p53 downstream of MDM2-mediated autophagy and apoptosis, suggesting that targeting CK1α provides a therapeutic opportunity to treat AML.

show abstract

“…Although multi-drug combinational chemotherapy can reduce the remission risk, relapse nevertheless is common. Accumulating evidence points to leukemia stem cells (LSCs) as the root of relapse [1, 2]. Thus, inducing damage to LSCs would be an effective approach to reduce the relapse rate of AML.…”

Section: Introductionmentioning

confidence: 99%

Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms

Tan

Zhang

Yuan

et al. 2019

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Background At present, it is generally believed that leukemia stem cells are the source of AML, so the killing of leukemia stem cells has become important. Previous studies have suggested that HHT combined with ATO can synergistically kill U937 cells, and HHT has also demonstrated the ability to kill leukemia stem cells. We evaluated whether HHT combined with ATO can systematically kill leukemia stem cells (LSCs) and explored the synergistic effect and molecular mechanism. Methods CCK-8 was used to detect cell viability. The changes of cell cycle (PI staining), apoptosis (Annexin V/PI) and surface markers (CD34, CD38, CD96, CD45) were detected by flow cytometry. The cells of CD34+ primary leukemia and CD38- KG-1, and TF-1 were separated by flow cytometry. High-throughput mRNA sequencing was used to analysis mRNA level changes after the application of the two drugs. Western blot was used to verify the changes of pathway protein expression. NRG mice were used as the receptor of xenograft model. Histological H&E staining assess the invaded ability of leukemia cells, and laser scanning confocal microscopy evaluated the molecule markers change. Results HHT and ATO synergistically killed KG-1 (CD34 + /CD96 + /CD38 + / − ) and Kasumi-1 (CD34 + /CD38 − ) cells. Their combination had a stronger effect of inducing apoptosis and blocking the cell cycle than HHT or ATO administrator alone, meanwhile significantly reducing the numbers of LSCs. Further, CD34 + CD38 − cells in KG-1, KG-1a, TF-1, and primary leukemia cells were more sensitive to HHT and ATO. High-throughput mRNA sequencing suggested that HHT alone could significantly upregulate molecules related to the Notch, P53, and NF-κB signaling pathways. When combined with ATO, HHT further upregulated P53, whereas HHT-induced NF-κB pathway activation was significantly suppressed. Western blot analysis verified the change of protein expression in the above pathways and further demonstrated that GSI, could eliminate these effects. In vivo, HHT combined with ATO significantly reduced the LSC burden, and weakened the expression of LSC markers. Conclusions This is the first evidence that HHT combined with arsenic can synergistically kill LSCs in vitro and in vivo, along with identification of the underlying mechanism, highlighting a potentially effective treatment strategy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1295-8) contains supplementary material, which is available to authorized users.

show abstract

JAM3 maintains leukemia-initiating cell self-renewal through LRP5/AKT/β-catenin/CCND1 signaling

Cited by 47 publications

References 52 publications

JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Response

JAM-C Expression as a Biomarker to Predict Outcome of Patients with Acute Myeloid Leukemia—Response

Casein kinase 1α inhibits p53 downstream of MDM2‑mediated autophagy and apoptosis in acute myeloid leukemia

Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms

Contact Info

Product

Resources

About