J Cancer 2020; 11(23):6768-6781. doi:10.7150/jca.46670

Research Paper

MLAA-34 knockdown shows enhanced antitumor activity via JAK2/STAT3 signaling pathway in acute monocytic leukemia

Bo Lei1#, Lu Qian2#, Yanping Zhang3, Yinxia Chen1, Meili Gao4, Walayat Shah5, Xingmei Cao1, Pengyu Zhang1, Wanhong Zhao1, Jie Liu1, Jianli Wang1, Xiaorong Ma1, Yun Yang1, Xin Meng1, Fengmei Cai6, Yan Xu1, Jing Luo7, Baiyan Wang1, Yang Zhang1, Aili He1✉, Wanggang Zhang1✉

1. Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Department of Hematology, 157 Xiwu Road, Xi'an, Shaanxi, China.
2. Department of Medical Research Center, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi Province, China, 710008.
3. Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Medical Laboratory, 157 Xiwu Road, Xi'an, Shaanxi, China.
4. Department of Biological Science and Engineering, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China, 710049.
5. Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan.
6. Xi'an No.4 Hospital, Department of Pathology, 21 Jiefang Road, Xi'an, Shaanxi, China.
7. Second Affiliated Hospital, Shaanxi University of traditional Chinese medicine, Department of Hematology, 5 Wei Yang west road, Xianyang, Shaanxi, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Lei B, Qian L, Zhang Y, Chen Y, Gao M, Shah W, Cao X, Zhang P, Zhao W, Liu J, Wang J, Ma X, Yang Y, Meng X, Cai F, Xu Y, Luo J, Wang B, Zhang Y, He A, Zhang W. MLAA-34 knockdown shows enhanced antitumor activity via JAK2/STAT3 signaling pathway in acute monocytic leukemia. J Cancer 2020; 11(23):6768-6781. doi:10.7150/jca.46670. Available from http://www.jcancer.org/v11p6768.htm

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MLAA-34 is a novel leukemia-associated gene closely related to the carcinogenesis of acute monocytic leukemia (AML). MLAA-34 over expression has been observed to inhibit apoptosis in vitro. JAK2/STAT3 pathway plays an important role in cell proliferation, differentiation and inhibition of apoptosis in number of cancers. However, the relationship and interaction between MLAA-34 and JAK2/STAT3 has never been investigated in AML.

This study investigates and reports a novel relationship between MLAA-34 and JAK2/STAT3 pathway in AML both in vitro and in vivo. We constructed MLAA-34 knockdown vector and transfected U937 cells to observe its apoptotic activities in relation to JAK2/STAT3 signaling pathway in vitro and then in vivo in mouse model. Levels of expression of MLAA-34 and JAK2/STAT3 and its downstream targets were also measured in AML patients and a few volunteers.

We found that MLAA-34 knockdown increased U937 apoptosis in vitro and inhibited tumor growth in vivo. Components of the canonical JAK2/STAT3 pathway or its downstream targets, including c-myc, bcl-2, Bax, and caspase-3, were shown to be involved in the carcinogenesis of AML. We also found that the JAK2/STAT3 pathway positively regulated MLAA-34 expression. We additionally identified a STAT3 binding site in the MLAA-34 promoter where STAT3 binds directly and activates MLAA-34 expression. In addition, MLAA-34 was found to form a complex with JAK2 and was enhanced by JAK2 activation. Correlation of MLAA-34 and JAK2/STAT3 was further confirmed in AML patients.

In conclusion, MLAA-34 is a novel regulator for JAK2/STAT3 signaling, and in turn, is regulated by this interaction in a positive feedback loop. Thus we report a novel model of interaction mechanism between MLAA-34 and JAK2/STAT3 which can be utilized as a potential target for a novel therapeutic approach in AML.

Keywords: acute monocytic leukemia, MLAA-34, JAK2/STAT3, positive feedback loop