Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V

被引：19

作者：

Rai, Shinya ^{[1
]}

Tanaka, Hirokazu ^{[1
]}

Suzuki, Mai ^{[2
]}

Espinoza, J. Luis ^{[1
]}

Kumode, Takahiro ^{[1
]}

Tanimura, Akira ^{[3
]}

Yokota, Takafumi ^{[3
]}

Oritani, Kenji ^{[4
]}

Watanabe, Toshio ^{[5
]}

Kanakura, Yuzuru ^{[3
]}

Matsumura, Itaru ^{[1
]}

机构：

[1] Kindai Univ, Fac Med, Dept Hematol & Rheumatol, Osaka, Japan

[2] Natl Canc Ctr, Div Hematol Malignancy, Chuo Ku, Tokyo, Japan

[3] Osaka Univ, Grad Sch Med, Dept Hematol & Oncol, Suita, Osaka, Japan

[4] Int Univ Hlth & Welf, Dept Hematol, Chiba, Japan

[5] Nara Womens Univ, Grad Sch Human & Sci, Dept Biol Sci, Nara, Nara, Japan

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

日本学术振兴会;

关键词：

C-KIT; STEM-CELL; CANCER; RECEPTOR; GENE; INHIBITORS; ENDOCYTOSIS; ACTIVATION; MUTATIONS; DOPAMINE;

D O I：

10.1038/s41467-020-17666-8

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：

Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD-or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34(+)CD38(-) AML cells including AML initiating cells with MT-RTKs in vitro and in vivo. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.

引用

页数：14

共 58 条

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