Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22

被引：53

作者：

Arruga, F. ^{[1
,2
]}

Gizdic, B. ^{[1
,2
]}

Bologna, C. ^{[1
,2
]}

Cignetto, S. ^{[1
,2
]}

Buonincontri, R. ^{[1
,2
]}

Serra, S. ^{[1
,2
]}

Vaisitti, T. ^{[1
,2
]}

Gizzi, K. ^{[1
]}

Vitale, N. ^{[3
]}

Garaffo, G. ^{[3
]}

Mereu, E. ^{[3
]}

Diop, F. ^{[4
]}

Neri, F. ^{[1
]}

Incarnato, D. ^{[1
]}

Coscia, M. ^{[3
]}

Allan, J. ^{[5
]}

Piva, R. ^{[3
]}

Oliviero, S. ^{[1
,6
]}

Furman, R. R. ^{[5
]}

Rossi, D. ^{[4
]}

Gaidano, G. ^{[4
]}

Deaglio, S. ^{[1
,2
]}

机构：

[1] Human Genet Fdn, Turin, Italy

[2] Univ Turin, Dept Med Sci, Turin, Italy

[3] Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy

[4] Univ Piemonte Orientale, Dept Translat Med, Div Hematol, Novara, Italy

[5] Weill Cornell Med, Dept Hematol, New York, NY USA

[6] Univ Turin, Dept Life Sci & Syst Biol, Turin, Italy

来源：

LEUKEMIA | 2017年 / 31卷 / 09期

关键词：

CLL; EXPRESSION; IMPACT; CANCER; TRANSFORMATION; LANDSCAPE; DNMT3A;

D O I：

10.1038/leu.2016.383

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.

引用

页码：1882 / 1893

页数：12

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