Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

被引：39

作者：

Zhang, Lianjun ^{[1
]}

Le Xuan Truong Nguyen ^{[1
]}

Chen, Ying-Chieh ^{[1
]}

Wu, Dijiong ^{[2
]}

Cook, Guerry J. ^{[1
]}

Dinh Hoa Hoang ^{[1
]}

Brewer, Casey J. ^{[1
]}

He, Xin ^{[1
]}

Dong, Haojie ^{[1
]}

Li, Shu ^{[3
]}

Li, Man ^{[1
]}

Zhao, Dandan ^{[1
]}

Qi, Jing ^{[1
]}

Hua, Wei-Kai ^{[1
]}

Cai, Qi ^{[1
]}

Carnahan, Emily ^{[1
]}

Chen, Wei ^{[4
]}

Wu, Xiwei ^{[4
]}

Swiderski, Piotr ^{[5
]}

Rockne, Russell C. ^{[6
]}

Kortylewski, Marcin ^{[7
]}

Li, Ling ^{[1
]}

Zhang, Bin ^{[1
]}

Marcucci, Guido ^{[1
]}

Kuo, Ya-Huei ^{[1
]}

机构：

[1] City Hope Med Ctr, Gehr Family Ctr Leukemia Res, Hematol Malignancies & Stem Cell Transplantat Ins, Dept Hematol Malignancies Translat Sci,Beckman Re, Duarte, CA 91010 USA

[2] Zhejiang Chinese Med Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310006, Zhejiang, Peoples R China

[3] Zhejiang Univ, Affiliated Hosp 2, Dept Hematol, Sch Med, Hangzhou 310009, Zhejiang, Peoples R China

[4] City Hope Med Ctr, Beckman Res Inst, Integrated Genom Core, Duarte, CA 91010 USA

[5] City Hope Med Ctr, Beckman Res Inst, Dept Mol Med, Duarte, CA 91010 USA

[6] City Hope Med Ctr, Beckman Res Inst, Dept Computat & Quantitat Med, Div Math Oncol, Duarte, CA 91010 USA

[7] City Hope Med Ctr, Beckman Res Inst, Dept Immunooncol, Duarte, CA 91010 USA

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

美国国家卫生研究院;

关键词：

CBF-BETA-SMMHC; CORE-BINDING FACTORS; NUCLEAR EXPORT; SELF-RENEWAL; FUSION GENE; C-MYC; MICRORNA; EXPRESSION; PROTEIN; TRANSCRIPTION;

D O I：

10.1038/s41467-021-26420-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML. miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients

引用

页数：17

共 71 条

[71] RUNX1 and CBFp-SMMHC transactivate target genes together in abnormal myeloid progenitors for leukemia development
Zhen, Tao
Cao, Yaqiang
Ren, Gang
Zhao, Ling
Hyde, R. Katherine
Lopez, Guadalupe
Feng, Dechun
Alemu, Lemlem
Zhao, Keji
Liu, P. Paul
[J]. BLOOD, 2020, 136 (21) : 2373 - 2385

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