Deficiency in Protein Tyrosine Phosphatase PTP1B Shortens Lifespan and Leads to Development of Acute Leukemia

被引：41

作者：

Le Sommer, Samantha ^{[1
]}

Morrice, Nicola ^{[1
]}

Pesaresi, Martina ^{[1
]}

Thompson, Dawn ^{[1
]}

Vickers, Mark A. ^{[1
]}

Murray, Graeme I. ^{[1
]}

Mody, Nimesh ^{[1
]}

Neel, Benjamin G. ^{[2
]}

Bence, Kendra K. ^{[3
]}

Wilson, Heather M. ^{[1
]}

Delibegovic, Mirela ^{[1
]}

机构：

[1] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland

[2] NYU, Laura & Isaac Perlmutter Canc Ctr, Langone Med Ctr, New York, NY USA

[3] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA

来源：

CANCER RESEARCH | 2018年 / 78卷 / 01期

基金：

英国惠康基金;

关键词：

HIGH-FAT DIET; T-CELL; INSULIN SENSITIVITY; MYELOMA CELLS; CANCER-CELLS; STAT3; MICE; ACTIVATION; 1B; EXPRESSION;

D O I：

10.1158/0008-5472.CAN-17-0946

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Protein tyrosine phosphatase PTP1B is a critical regulator of signaling pathways controlling metabolic homeostasis, cell proliferation, and immunity. In this study, we report that global or myeloid-specific deficiency of PTP1B in mice decreases lifespan. We demonstrate that myeloid-specific deficiency of PTP1B is sufficient to promote the development of acutemyeloid leukemia. LysM-PTP1B(-/-) mice lacking PTP1B in the innate myeloid cell lineage displayed a dysregulation of bone marrow cells with a rapid decline in population at midlife and a concomitant increase in peripheral blood blast cells. This phenotype manifested further with extramedullary tumors, hepatic macrophage infiltration, and metabolic reprogramming, suggesting increased hepatic lipid metabolism prior to overt tumor development. Mechanistic inves-tigations revealed an increase in anti-inflammatory M2 macrophage responses in liver and spleen, as associated with increased expression of arginase I and the cytokines IL10 and IL4. We also documented STAT3 hypersphosphorylation and signaling along with JAK-dependent upregulation of antiapoptotic proteins Bcl2 and BclXL. Our results establish a tumor suppressor role for PTP1B in the myeloid lineage cells, with evidence that its genetic inactivation in mice is sufficient to drive acute myeloid leukemia. (C) 2017 AACR.

引用

页码：75 / 87

页数：13

共 49 条

[21] Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice [J].