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Shp2 and Pten Have Antagonistic Roles in Myeloproliferation but Cooperate to Promote Erythropoiesis in Mammals

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Shp2 and Pten Have Antagonistic Roles in Myeloproliferation but Cooperate to Promote Erythropoiesis in Mammals Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals Helen He Zhua,b,1, Xiaolin Luob, Kaiqing Zhanga, Jian Cuia, Huifang Zhaoa, Zhongzhong Jia, Zhicheng Zhoua, Jufang Yaoa, Lifan Zengc, Kaihong Jib, Wei-Qiang Gaoa,d, Zhong-Yin Zhangc, and Gen-Sheng Fengb,1 aState Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; bDepartment of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0864; cDepartment of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; and dSchool of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, and approved September 18, 2015 (received for review April 21, 2015) Previous data suggested a negative role of phosphatase and tensin Furthermore, hematopoietic disorders, mainly MPN, were detected homolog (Pten) and a positive function of SH2-containing tyrosine in transgenic or knockin mouse lines expressing the dominant-active phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Shp2 mutants (22, 23). In aggregate, these data suggest opposite Herein we demonstrate that ablating Shp2 indeed suppressed the roles of Pten and Shp2 in myelopoiesis. myeloproliferative effect of Pten loss, indicating directly opposing The present study is designed to determine functional interactions functions between pathways regulated by these two enzymes. Sur- between Pten- and Shp2-modulated signaling cascades in hemato- prisingly, the Shp2 and Pten double-knockout mice suffered lethal poietic cell lineages. anemia, a phenotype that reveals previously unappreciated coopera- Results tive roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and short- Additional Deletion of Shp2 Suppresses MPN Induced by Pten Loss. We generated a new mouse line with conditional deletion of ened erythrocyte lifespan. Consistently, treatment of Pten-deficient + both Pten and Shp2 in the hematopoietic compartment [Cre : mice with a specific Shp2 inhibitor suppressed myeloproliferative neo- fl/fl fl/fl fl/fl Pten :Shp2 , double knockout (DKO)], by crossing Pten plasm while causing anemia. These results identify concerted actions Shp2fl/fl Mx1-Cre of Pten and Shp2 in promoting erythropoiesis, while acting antago- and mice with transgenic mice. Polyinosine- nistically in myeloproliferative neoplasm development. This study il- polycytidine (poly-I:C) injection induced efficiently Cre-medi- ated DNA excision at both Pten and Shp2 loci in bone marrow lustrates cell type-specific signal cross-talk in blood cell lineages, and (BM) cells (Fig. 1 A and B). In agreement with previous data will guide better design of pharmaceuticals for leukemia and other + fl/fl (8, 9), the conditional Pten KO (PKO) (Cre :Pten ) animals types of cancer in the era of precision medicine. displayed significantly elevated counts of total white blood cells (WBC), lymphocytes, monocytes, and granulocytes, with the Pten | Shp2 | myeloproliferative neoplasm | erythropoiesis | anemia latter exhibiting the most drastic increase (Fig. 1C). However, + fl/fl the inducible Shp2 KO (SKO) (Cre :Shp2 ) mice exhibited elineating molecular signaling cascades has guided the de- opposite phenotypes of lowering blood cell counts, reinforcing a Dsign of many therapeutic chemicals that target specific sig- positive role for Shp2 in promoting hematopoiesis (Fig. 1C). naling molecules for treatment of various diseases, including cancer. Notably, dual deletion of Pten and Shp2 restored overall and spe- However, the cross-talk between signaling pathways may confound cific WBC counts to nearly WT levels (Fig. 1C), indicating opposing patients’ responses to pharmaceuticals designed to disrupt a specific pathway. For example, AXL kinase activation leads to resistance Significance to erlotinib that targets EGFR in treatment of non-small cell lung cancer (1). This issue can be even more complicated by the Despite the extensive attentions paid to phosphatase and tensin possibility that parallel pathways may work cooperatively or antag- homolog (Pten) or SH2-containing tyrosine phosphatase (Shp2) onistically, depending on cellular context. Thus, elucidating cell type- functions in cell signaling, how their regulated pathways are specific signal intersections will be instrumental for predicting and intertwined has never been investigated. By creating a com- alleviating side effects and also for designing optimal drug mixtures. pound mutant mouse line with both genes deleted in blood Pten (phosphatase and tensin homolog) is a tumor suppressor cells, we have found that Pten and Shp2 can work antagonisti- that negatively regulates the phosphoinositide 3-kinase (PI3K) and cally in myelopoiesis, while acting cooperatively in erythropoi- Akt pathway and is frequently mutated in hematopoietic malig- esis. Consistently, pharmacological inhibition of Shp2 suppressed nancies, especially in T-cell lymphoblastic leukemia, and acute myeloproliferative neoplasm induced by Pten loss but induced – myeloid leukemia (2 7). Consistently, selective deletion of Pten in severe anemia. These data explain why some pharmaceuticals blood cells resulted in short-term expansion and long-term decline designed to target a specific pathway can suppress one patho- of hematopoietic stem cells (HSC), as well as development of my- genic process but trigger another. eloproliferative neoplasm (MPN), defining a preventive role of Pten in myeloproliferative disorders (8, 9). In contrast, Shp2 is an SH2- Author contributions: H.H.Z. and G.-S.F. designed research; H.H.Z., X.L., K.Z., J.C., H.Z., Z.J., containing tyrosine phosphatase that plays a positive role in he- Z.Z., and K.J. performed research; J.Y., L.Z., and Z.-Y.Z. contributed new reagents/analytic matopoiesis, and ablating Shp2 suppressed HSC and progenitor cell tools; H.H.Z., X.L., L.Z., and Z.-Y.Z. analyzed data; and H.H.Z., W.-Q.G., and G.-S.F. wrote self-renewal and differentiation in mice (10–12). Dominantly acti- the paper. vating mutations were detected in Ptpn11/Shp2 in nearly 50% of The authors declare no conflict of interest. Noonan syndrome patients (13–16), who have higher risk of juvenile This article is a PNAS Direct Submission. myelomonocytic leukemia (13, 17, 18). Somatic gain-of-function 1To whom correspondence may be addressed. Email: [email protected] or mutations in Ptpn11/Shp2 have been detected in sporadic juvenile [email protected]. myelomonocytic leukemia, acute myeloid leukemia, B-cell This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. lymphoblastic leukemia, and myelodysplastic syndromes (19–21). 1073/pnas.1507599112/-/DCSupplemental. 13342–13347 | PNAS | October 27, 2015 | vol. 112 | no. 43 www.pnas.org/cgi/doi/10.1073/pnas.1507599112 Downloaded by guest on September 28, 2021 Fig. 1. Shp2 ablation neutralizes development of myeloid proliferative neoplasm induced by Pten loss. (A) A Pten and Shp2 DKO mouse line was + generated by breeding Mx1-Cre :Ptenfl/fl:Shp2fl/fl − with Mx1-Cre :Ptenfl/fl:Shp2fl/fl mice and injection of poly-I:C. (B) Excision of the floxed DNA sequences was detected by PCR analysis of BM cells isolated 1 wk after final poly-I:C injection. (C) WBC, lym- phocyte (LYM), monocyte (MON), and granulocyte (GRA) count in the peripheral blood was performed 1 wk after final poly-I:C injection (n = 5–8). (D) Representative FACS plots for Mac1 and Gr1 staining of BM cells. (E) Shp2 ablation suppresses Pten deletion-mediated accumulation of Mac1+Gr1+ BM cells (n = 3–5). (F) Shp2 removal restrains over- + proliferation of splenic Gr1 cells induced by Pten deficiency (n = 3–4). (G) Representative H&E staining of spleen sections. Images were scanned by Scan- Scope Digital Slide Scanners with 100× magnification. (H) Representative chloroacetate esterase staining of liver sections shows myeloid infiltration in PKO but not DKO liver. Arrows point to the myeloid cells. Images were scanned by ScanScope Digital Slide Scanners with 100× magnification. (***P < 0.001, **P < 0.01, *P < 0.05; data are presented as means ± SEM.) roles for Shp2 and Pten in myelopoiesis. In particular, addi- with previous reports by other groups (8, 9), we found that Pten tional removal of Shp2 normalized the expansion of Pten-deficient deficiency led to extramedullary hematopoiesis manifested by sub- + + Mac1 Gr1 myeloid progenitors (Fig. 1 D and E), and suppressed stantial increase in spleen-derived myeloid colonies but unchanged − − + excessive proliferation of Pten / Gr1 cells in the spleen (Fig. 1F). BM-derived myeloid colonies using in vitro CFU-C assays (Fig. 2 E Extramedullary hematopoiesis in PKO spleen disrupted the normal and F and Fig. S1). Additional Shp2 removal abolished the increase red-pulp/white-pulp structure, which was also partially rescued in and restored spleen- or BM-derived myeloid colonies to almost WT DKO mice (Fig. 1G). Chloroacetate esterase staining showed ap- levels in general (Fig. 2 E and F and Fig. S1). Taken together, these parent myeloid cell infiltration in the liver of PKO but not DKO data suggest a role of Shp2 in promoting myeloid proliferation
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