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Dual Requirement for the ETS Transcription Factors Fli-1 and Erg in Hematopoietic Stem Cells and the Megakaryocyte Lineage

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Dual Requirement for the ETS Transcription Factors Fli-1 and Erg in Hematopoietic Stem Cells and the Megakaryocyte Lineage Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage Elizabeth A. Krusea,b, Stephen J. Loughranb,c, Tracey M. Baldwina, Emma C. Josefssona, Sarah Ellisd, Dennis K. Watsone, Paquita Nurdenf, Donald Metcalfc, Douglas J. Hiltona,b, Warren S. Alexanderc, and Benjamin T. Kilea,1 Divisions of aMolecular Medicine and cCancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Australia; bDepartment of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia; dPeter MacCallum Cancer Centre, St. Andrew’s Place, East Melbourne 3002, Australia; ePathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425; and fCentre de Re´fe´ rence des Pathologies Plaquettaires, Plateforme Technologique et d’Innovation Biome´dicale, Hoˆpital Xavier Arnozan, 33600 Pessac, France Contributed by Donald Metcalf, June 16, 2009 (sent for review May 4, 2009) Fli-1 and Erg are closely related members of the Ets family of in hematopoiesis, with a specific requirement for both genes transcription factors. Both genes are translocated in human can- evident in the regulation of HSC number and function, and in the cers, including Ewing’s sarcoma, leukemia, and in the case of Erg, development of the megakaryocyte lineage. more than half of all prostate cancers. Although evidence from mice and humans suggests that Fli-1 is required for megakaryo- Results poiesis, and that Erg is required for normal adult hematopoietic A Genetic Interaction Between Fli-1 and Erg. To examine the rela- stem cell (HSC) regulation, their precise physiological roles remain tionship between Erg and Fli-1 at the genetic level, we crossed mice to be defined. To elucidate the relationship between Fli-1 and Erg heterozygous for a targeted deletion of the Fli-1 C-terminal acti- in hematopoiesis, we conducted an analysis of mice carrying vation domain (5) with mice heterozygous for the ErgMld2 allele, mutations in both genes. Our results demonstrate that there is a which encodes a point mutation in the DNA-binding Ets domain of profound genetic interaction between Fli-1 and Erg. Double het- Erg. At weaning, Fli-1ϩ/Ϫ Ergϩ/ϩ (hereafter referred to as Fli-1ϩ/Ϫ) erozygotes displayed phenotypes more dramatic than single het- and Fli-1ϩ/ϩ Ergϩ/Mld2 (hereafter referred to as Ergϩ/Mld2) mice were CELL BIOLOGY erozygotes: severe thrombocytopenia, with a significant deficit in observed at the expected Mendelian ratios, however, only half the megakaryocyte numbers and evidence of megakaryocyte dysmor- expected number of Fli-1ϩ/Ϫ Ergϩ/Mld2 mice were present (ob- phogenesis, and loss of HSCs accompanied by a reduction in the served/expected ratios were: Fli-1ϩ/ϩ Erg ϩ/ϩ 1.2:1, Fli-1ϩ/Ϫ 1.1:1, number of committed hematopoietic progenitor cells. These results Ergϩ/Mld2 1.1:1, and Fli-1ϩ/Ϫ Ergϩ/Mld2 0.6:1). Mice of all genotypes illustrate an indispensable requirement for both Fli-1 and Erg in appeared outwardly healthy, and a histopathological survey of normal HSC and megakaryocyte homeostasis, and suggest these tissues in 8-week-old mice showed no gross abnormalities in the transcription factors may coregulate common target genes. thymus, spleen, pancreas, lymph nodes, liver, kidney, bladder, small bowel, skin, or salivary gland. We then examined peripheral blood he E-twenty-six specific (Ets) proteins are a family of more than at 8 to 10 weeks of age. As described, Ergϩ/Mld2 mice exhibit a mild T20 helix–loop–helix domain transcription factors that have been thrombocytopenia (12) (Table 1). The peripheral blood counts of implicated in a myriad of cellular processes (1). Fli-1 and Erg are Fli-1ϩ/Ϫ mice were normal. In contrast, Fli-1ϩ/Ϫ Ergϩ/Mld2 mice Ets proteins that share greater homology to each other than to other exhibited severe thrombocytopenia (platelet counts Ϸ25% that Ets family members. Fli-1 is mutated in a number of cancers, observed in Ergϩ/Mld2 mice) and pancytopenia with deficits of including Ewing’s sarcoma and erythroleukemia (2, 3). Genetic 10–50% in red blood cells and white blood cells including manipulation in mice (4, 5) and mutations in humans (4, 6) have lymphocytes, neutrophils, monocytes and eosinophils (Table 1 revealed multiple roles for Fli-1 in hematopoiesis including the and Fig. 1A). production of megakaryocytes and platelets. Fli-1 is also implicated in the regulation of important stem cell genes, suggesting a role Fli-1 and Erg Are Required for Normal Megakaryopoiesis. To establish within the hematopoietic stem cell compartment (7, 8). Erg is also whether a defect in platelet production was responsible for the a proto-oncogene, translocated in Ewing sarcoma, leukemia, and observed thrombocytopenia, we examined megakaryopoiesis. Nor- prostate cancer (9–11). We recently reported a mouse model of Erg mal numbers of megakaryocytes were observed in the bone marrow dysfunction, ErgMld2, in which an N-ethyl-N-nitrosourea (ENU)- of Fli-1ϩ/Ϫ mice. Compared with wild-type controls, the bone induced point mutation causes profound loss of Erg function. These marrow of Ergϩ/Mld2 mice demonstrated a modest but significant mice revealed an indispensable requirement for Erg in definitive reduction in the number of megakaryocytes, consistent with their hematopoiesis with ErgMld2/Mld2 embryos dying at midgestation. mild thrombocytopenia. In contrast, the number of megakaryo- Analyses of Ergϩ/Mld2 adult mice revealed that Erg is required for cytes in Fli-1ϩ/Ϫ Ergϩ/Mld2 bone marrow was Ͻ25% that seen in normal adult HSC homeostasis. HSCs are reduced in number in Ergϩ/Mld2 mice and a similar trend was also observed in the spleen Ergϩ/Mld2 mice and unable to compete effectively with Ergϩ/ϩ cells (Fig. 1B). The number of megakaryocyte progenitor cells in to reconstitute irradiated transplant recipients (12). Fli-1ϩ/Ϫ Ergϩ/Mld2 bone marrow and spleen was reduced to a greater In translocations driving Ewing’s sarcoma, Fli-1 and Erg appear to be interchangeable; either Fli-1 or Erg can fuse with the gene encoding an RNA binding protein, EWS, and give rise Author contributions: E.A.K., S.J.L., E.C.J., D.J.H., W.S.A., and B.T.K. designed research; E.A.K., T.M.B., S.E., W.S.A., and B.T.K. performed research; D.K.W. contributed new re- to clinically indistinguishable disease (13). Moreover, in vitro agents/analytic tools; E.A.K., S.J.L., E.C.J., S.E., P.N., D.M., D.J.H., W.S.A., and B.T.K. analyzed data suggests that Fli-1 and Erg may heterodimerize to regulate data; and E.A.K., W.S.A., and B.T.K. wrote the paper. sets of overlapping target genes (14, 15), raising the prospect that The authors declare no conflict of interest. these proteins may, in part, be redundant. To explore the 1To whom correspondence may be addressed. E-mail: [email protected] or metcalf@ relationship between Fli-1 and Erg in a physiological setting, we wehi.edu.au. analyzed mice heterozygous for mutations in both genes. We This article contains supporting information online at www.pnas.org/cgi/content/full/ observed a profound genetic interaction between Fli-1 and Erg 0906556106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0906556106 PNAS Early Edition ͉ 1of6 Downloaded by guest on September 29, 2021 Table 1. Peripheral blood counts Fli-1ϩ/ϩ Ergϩ/ϩ Fli-1ϩ/Ϫ Ergϩ/Mld2 Fli-1ϩ/Ϫ Ergϩ/Mld2 n ϭ 16 n ϭ 16 n ϭ 16 n ϭ 16 Platelets (ϫ 106/mL) 1146 Ϯ 162 986 Ϯ 163 898 Ϯ 138† 202 Ϯ 130* Erythrocytes (ϫ 109/mL) 9.8 Ϯ 0.9 10.6 Ϯ 0.5␸ 10.4 Ϯ 1.1 8.7 Ϯ 0.7* Hematocrit, % 47.8 Ϯ 5.5 52.4 Ϯ 2.3␸ 50.7 Ϯ 5.3 44.1 Ϯ 4.6* Leukocytes (ϫ 106/mL) 5.8 Ϯ 2.3 6.9 Ϯ 1.8 5.3 Ϯ 1.9 2.9 Ϯ 1.4* Neutrophils (ϫ 106/mL) 0.78 Ϯ 0.45 0.46 Ϯ 0.20 0.60 Ϯ 0.43 0.21 Ϯ 0.14* Lymphocytes (ϫ 106/mL) 4.4 Ϯ 2.2 6.0 Ϯ 1.5 4.4 Ϯ 1.8 2.5 Ϯ 1.3* Monocytes (ϫ 106/mL) 0.37 Ϯ 0.59 0.21 Ϯ 0.27 0.16 Ϯ 0.14 0.07 Ϯ 0.12 Eosinophils (ϫ 106/mL) 0.10 Ϯ 0.05 0.08 Ϯ 0.04 0.11 Ϯ 0.04 0.02 Ϯ 0.01* Peripheral blood counts from 8- to 10-week-old mice. Data represent mean Ϯ SD. ␸, P Ͻ 0.05 for comparison of data from Fli-1ϩ/ϩ Ergϩ/ϩ with that of Fli-1ϩ/Ϫ mice. †, P Ͻ 0.05 for comparison of data from Fli-1ϩ/ϩErgϩ/ϩ with ϩ ϩ ϩ Ϫ ϩ that of Erg /Mld2 mice. *, P Ͻ 0.05 for comparison of data from Erg /Mld2 with that of Fli-1 / Erg /Mld2 mice with Bonferroni correction for multiple testing. extent than that of megakaryocytes. A more modest reduction in that a deficit in production of the major cytokine regulator of megakaryocyte progenitor cells was evident in the tissues of Ergϩ/ steady-state megakaryopoiesis could not account for the defective ϩ Ϫ Mld2 mice, as described in ref. 12. In Fli-1 / mice, the numbers of megakaryopoiesis observed in these mice. these cells was normal (Fig. 1C and Table 2). Normal levels of TPO were detected in the serum of Fli-1ϩ/Ϫ Ergϩ/Mld2 mice, suggesting Increased Platelet Clearance in Fli-1؉/؊ Erg؉/Mld2 Mice.
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