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• W1982901636 abstract "The subset of acute myeloid leukemias (AML) with chromosomal translocations involving the MLL gene have a poor prognosis (referred to as 11q23-AML). The MLL fusion proteins that are expressed in 11q23-AML facilitate transcription of a set of HOX genes, including HOXA9 and HOXA10. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. In the current study we found that Mll-Ell (an MLL fusion protein) induced transcriptional activation of the FGF2 gene in a HoxA9- and HoxA10-dependent manner. FGF2 encodes fibroblast growth factor 2 (also referred to as basic fibroblast growth factor). Fgf2 influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2-expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf2 and Fgf2-dependent cytokine hypersensitivity. Therefore, our results implicated increased Fgf2 expression in progenitor proliferation and expansion in 11q23-AML. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia.Background: MLL fusion proteins, including Mll-Ell, induce overexpression of HoxA9 and HoxA10 in the bone marrow.Results: Mll-Ell induces HoxA9-and HoxA10-dependent FGF2 transcription. Autocrine production of Fgf2 contributes to cytokine hypersensitivity in Mll-Ell expressing myeloid progenitor cells.Conclusion: Mll-Ell induces Fgf2 production by myeloid progenitors and differentiating myeloid cells.Significance: Proliferative effects of Fgf2 may influence the pathogenesis of leukemias with MLL gene translocations. The subset of acute myeloid leukemias (AML) with chromosomal translocations involving the MLL gene have a poor prognosis (referred to as 11q23-AML). The MLL fusion proteins that are expressed in 11q23-AML facilitate transcription of a set of HOX genes, including HOXA9 and HOXA10. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. In the current study we found that Mll-Ell (an MLL fusion protein) induced transcriptional activation of the FGF2 gene in a HoxA9- and HoxA10-dependent manner. FGF2 encodes fibroblast growth factor 2 (also referred to as basic fibroblast growth factor). Fgf2 influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2-expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf2 and Fgf2-dependent cytokine hypersensitivity. Therefore, our results implicated increased Fgf2 expression in progenitor proliferation and expansion in 11q23-AML. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia. Background: MLL fusion proteins, including Mll-Ell, induce overexpression of HoxA9 and HoxA10 in the bone marrow. Results: Mll-Ell induces HoxA9-and HoxA10-dependent FGF2 transcription. Autocrine production of Fgf2 contributes to cytokine hypersensitivity in Mll-Ell expressing myeloid progenitor cells. Conclusion: Mll-Ell induces Fgf2 production by myeloid progenitors and differentiating myeloid cells. Significance: Proliferative effects of Fgf2 may influence the pathogenesis of leukemias with MLL gene translocations. Clinical correlative studies defined a poor prognosis subset of acute myeloid leukemia (AML) 2The abbreviations used are: AML, acute myeloid leukemia; HSC, hematopoietic stem cell; Fgf2, fibroblast growth factor 2; HD, homeodomain; RA, retinoic acid; DMF, dimethylformamide; GMP, granulocyte/monocyte progenitor cell; SCF, stem cell factor. with increased expression of HoxB3, HoxB4, HoxA9–11, and Meis1 in CD34+ bone marrow cells (1.Kawagoe H. Humphries R.K. Blair A. Sutherland H.J. Hogge D.E. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.Leukemia. 1999; 13: 687-698Crossref PubMed Scopus (181) Google Scholar). In this leukemia subset, expression of these proteins was also aberrantly sustained in differentiating, CD34− myeloid cells. Further analysis determined that this pattern of gene expression was characteristic of AML with chromosomal translocations or partial tandem duplications involving the MLL gene (referred to as 11q23-AML), chromosomal translocation involving the MYST3 and CREBBP genes, and a poor prognosis subset of cytogenetically normal AML (2.Armstrong S.A. Staunton J.E. Silverman L.B. Pieters R. den Boer M.L. Minden M.D. Sallan S.E. Lander E.S. Golub T.R. Korsmeyer S.J. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.Nat. Genet. 2002; 30: 41-47Crossref PubMed Scopus (1603) Google Scholar, 3.Guenther M.G. Jenner R.G. Chevalier B. Nakamura T. Croce C.M. Canaani E. Young R.A. Global and Hox-specific roles for the MLL1 methyltransferase.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 8603-8608Crossref PubMed Scopus (277) Google Scholar, 4.Milne T.A. Briggs S.D. Brock H.W. Martin M.E. Gibbs D. Allis C.D. Hess J.L. MLL targets SET domain methyltransferase activity to Hox gene promoters.Mol. Cell. 2002; 10: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (867) Google Scholar, 5.Ernst P. Mabon M. Davidson A.J. Zon L.I. Korsmeyer S.J. An Mll-dependent Hox program drives hematopoietic progenitor expansion.Curr. Biol. 2004; 14: 2063-2069Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 6.Camós M. Esteve J. Jares P. Colomer D. Rozman M. Villamor N. Costa D. Carrió A. Nomdedéu J. Montserrat E. Campo E. Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression.Cancer Res. 2006; 66: 6947-6954Crossref PubMed Scopus (118) Google Scholar, 7.Roche J. Zeng C. Barón A. Gadgil S. Gemmill R.M. Tigaud I. Thomas X. Drabkin H.A. Hox expression in AML identified a distinct subset of patients with intermediate cytogenetics. Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics.Leukemia. 2004; 18: 1059-1063Crossref PubMed Scopus (48) Google Scholar). More than 20 different fusion partners have been described for the MLL gene in 11q23-AML (2.Armstrong S.A. Staunton J.E. Silverman L.B. Pieters R. den Boer M.L. Minden M.D. Sallan S.E. Lander E.S. Golub T.R. Korsmeyer S.J. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.Nat. Genet. 2002; 30: 41-47Crossref PubMed Scopus (1603) Google Scholar). The expressed MLL fusion proteins include common N-terminal domains from MLL and C-terminal domains from the various different partner genes. Studies in murine models supported a functional role for MLL fusion proteins in Hox expression and leukemia. Engineered expression of various MLL fusion proteins in murine bone marrow cells increased Hox expression in a manner that was consistent with human 11q23-AML (1.Kawagoe H. Humphries R.K. Blair A. Sutherland H.J. Hogge D.E. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.Leukemia. 1999; 13: 687-698Crossref PubMed Scopus (181) Google Scholar, 5.Ernst P. Mabon M. Davidson A.J. Zon L.I. Korsmeyer S.J. An Mll-dependent Hox program drives hematopoietic progenitor expansion.Curr. Biol. 2004; 14: 2063-2069Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 8.Li Z. Luo R.T. Mi S. Sun M. Chen P. Bao J. Neilly M.B. Jayathilaka N. Johnson D.S. Wang L. Lavau C. Zhang Y. Tseng C. Zhang X. Wang J. Yu J. Yang H. Wang S.M. Rowley J.D. Chen J. Thirman M.J. Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.Cancer Res. 2009; 69: 1109-1116Crossref PubMed Scopus (71) Google Scholar). MLL fusion proteins also expanded the hematopoietic stem cell (HSC) and myeloid progenitor cell bone marrow populations in vitro and induced a myeloproliferative neoplasm that progressed to AML over time in vivo (1.Kawagoe H. Humphries R.K. Blair A. Sutherland H.J. Hogge D.E. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.Leukemia. 1999; 13: 687-698Crossref PubMed Scopus (181) Google Scholar, 5.Ernst P. Mabon M. Davidson A.J. Zon L.I. Korsmeyer S.J. An Mll-dependent Hox program drives hematopoietic progenitor expansion.Curr. Biol. 2004; 14: 2063-2069Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 8.Li Z. Luo R.T. Mi S. Sun M. Chen P. Bao J. Neilly M.B. Jayathilaka N. Johnson D.S. Wang L. Lavau C. Zhang Y. Tseng C. Zhang X. Wang J. Yu J. Yang H. Wang S.M. Rowley J.D. Chen J. Thirman M.J. Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.Cancer Res. 2009; 69: 1109-1116Crossref PubMed Scopus (71) Google Scholar). These results were similar with all of the MLL fusion proteins tested. Other murine models supported a functional role for Hox proteins in leukemogenesis. Human and murine HOX genes are clustered in four groups (A-D) on four chromosomes (9.Acampora D. D'Esposito M. Faiella A. Pannese M. Migliaccio E. Morelli F. Stornaiuolo A. Nigro V. Simeone A. Boncinelli E. The human HOX gene family.Nucleic Acids Res. 1989; 17: 10385-10402Crossref PubMed Scopus (268) Google Scholar, 10.Sauvageau G. Lansdorp P.M. Eaves C.J. Hogge D.E. Dragowska W.H. Reid D.S. Largman C. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 12223-12227Crossref PubMed Scopus (441) Google Scholar). HOX1–4 genes are most highly transcribed in HSC, and transcription of HOX7–11 is most active in committed progenitor cells (10.Sauvageau G. Lansdorp P.M. Eaves C.J. Hogge D.E. Dragowska W.H. Reid D.S. Largman C. Differential expression of homeobox genes in functionally distinct CD34+ subpopulations of human bone marrow cells.Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 12223-12227Crossref PubMed Scopus (441) Google Scholar). Consistent with this expression profile, engineered overexpression of HoxB3 or HoxB4 in murine bone marrow expanded the HSC population and led to an myeloproliferative neoplasm in vivo (11.Thorsteinsdottir U. Kroon E. Jerome L. Blasi F. Sauvageau G. Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia.Mol. Cell. Biol. 2001; 21: 224-234Crossref PubMed Scopus (226) Google Scholar, 12.Sauvageau G. Thorsteinsdottir U. Eaves C.J. Lawrence H.J. Largman C. Lansdorp P.M. Humphries R.K. Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo.Genes Dev. 1995; 9: 1753-1765Crossref PubMed Scopus (506) Google Scholar). Overexpression of either HoxA9 or HoxA10 in murine bone marrow was characterized by expansion of the bipotential myeloid progenitor population (granulocyte/monocyte progenitors (GMP)) (13.Calvo K.R. Sykes D.B. Pasillas M. Kamps M.P. Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression.Mol. Cell. Biol. 2000; 20: 3274-3285Crossref PubMed Scopus (117) Google Scholar, 14.Lawrence H.J. Helgason C.D. Sauvageau G. Fong S. Izon D.J. Humphries R.K. Largman C. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.Blood. 1997; 89: 1922-1930Crossref PubMed Google Scholar, 15.Buske C. Feuring-Buske M. Antonchuk J. Rosten P. Hogge D.E. Eaves C.J. Humphries R.K. Overexpression of HOXA10 perturbs human lymphomyelopoiesis in vitro and in vivo.Blood. 2001; 97: 2286-2292Crossref PubMed Scopus (90) Google Scholar, 16.Björnsson J.M. Andersson E. Lundström P. Larsson N. Xu X. Repetowska E. Humphries R.K. Karlsson S. Proliferation of primitive myeloid progenitors can be reversibly induced by HOXA10.Blood. 2001; 98: 3301-3308Crossref PubMed Scopus (42) Google Scholar, 17.Thorsteinsdottir U. Mamo A. Kroon E. Jerome L. Bijl J. Lawrence H.J. Humphries K. Sauvageau G. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion.Blood. 2002; 99: 121-129Crossref PubMed Scopus (290) Google Scholar). In vivo overexpression of HoxA9 or HoxA10 resulted in an myeloproliferative neoplasm that evolved to AML in a manner similar to MLL fusion proteins (1.Kawagoe H. Humphries R.K. Blair A. Sutherland H.J. Hogge D.E. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells.Leukemia. 1999; 13: 687-698Crossref PubMed Scopus (181) Google Scholar, 17.Thorsteinsdottir U. Mamo A. Kroon E. Jerome L. Bijl J. Lawrence H.J. Humphries K. Sauvageau G. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion.Blood. 2002; 99: 121-129Crossref PubMed Scopus (290) Google Scholar, 18.Wang H. Lindsey S. Konieczna I. Bei L. Horvath E. Huang W. Saberwal G. Eklund E.A. Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia.J. Biol. Chem. 2009; 284: 2549-2567Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 19.Kroon E. Krosl J. Thorsteinsdottir U. Baban S. Buchberg A.M. Sauvageau G. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b.EMBO J. 1998; 17: 3714-3725Crossref PubMed Scopus (543) Google Scholar). These studies suggested the possibility that Hox proteins were involved in expansion of the leukemia stem cell population in 11q23-AML. In various forms of AML this population has generally been defined as a GMP with HSC-like characteristics (20.Goardon N. Marchi E. Atzberger A. Quek L. Schuh A. Soneji S. Woll P. Mead A. Alford K.A. Rout R. Chaudhury S. Gilkes A. Knapper S. Beldjord K. Begum S. Rose S. Geddes N. Griffiths M. Standen G. Sternberg A. Cavenagh J. Hunter H. Bowen D. Killick S. Robinson L. Price A. Macintyre E. Virgo P. Burnett A. Craddock C. Enver T. Jacobsen S.E. Porcher C. Vyas P. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.Cancer Cell. 2011; 19: 138-152Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar). However, the set of Hox target genes that mediated bone marrow progenitor expansion was not defined. We used chromatin immunoprecipitation-based screening techniques to identify HoxA10 target genes that might be relevant to leukemogenesis (21.Wang H. Lu Y. Huang W. Papoutsakis E.T. Fuhrken P. Eklund E.A. HoxA10 activates transcription of the gene encoding mitogen-activated protein kinase phosphatase 2 (Mkp2) in myeloid cells.J. Biol. Chem. 2007; 282: 16164-16176Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 22.Bei L. Lu Y. Bellis S.L. Zhou W. Horvath E. Eklund E.A. Identification of a HoxA10 activation domain necessary for transcription of the gene encoding β3 integrin during myeloid differentiation.J. Biol. Chem. 2007; 282: 16846-16859Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 23.Shah C.A. Wang H. Bei L. Platanias L.C. Eklund E.A. HoxA10 regulates transcription of the gene encoding transforming growth factor β2 (TGFB2) in myeloid cells.J. Biol. Chem. 2011; 286: 3161-3176Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 24.Wang H. Bei L. Shah C.A. Horvath E. Eklund E.A. HoxA10 influences protein ubiquitination by activating transcription of ARIH2; the gene encoding Triad1.J. Biol. Chem. 2011; 286: 16832-16845Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 25.Bei L. Huang W. Wang H. Shah C. Horvath E. Eklund E. HoxA10 activates CDX4 transcription and Cdx4 activates HOXA10 transcription in myeloid cells.J. Biol. Chem. 2011; 286: 19047-19064Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). In these studies we identified the gene encoding fibroblast growth factor 2 (Fgf2, or basic Fgf) as a HoxA10 target gene (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Fgf2 is produced by bone marrow stromal cells, hematopoietic progenitor cells, and mature phagocytes (27.Yoon S.Y. Tefferi A. Li C.Y. Cellular distribution of platelet-derived growth factor, transforming growth factor-β, basic fibroblast growth factor, and their receptors in normal bone marrow.Acta Haematol. 2000; 104: 151-157Crossref PubMed Scopus (48) Google Scholar). Increased Fgf2 production by AML cells is described, and a search of publically available data bases specifically associated this with 11q23-AML (28.Aguayo A. Kantarjian H. Manshouri T. Gidel C. Estey E. Thomas D. Koller C. Estrov Z. O'Brien S. Keating M. Freireich E. Albitar M. Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes.Blood. 2000; 96: 2240-2245Crossref PubMed Google Scholar, 29.Rhodes D.R. Yu J. Shanker K. Deshpande N. Varambally R. Ghosh D. Barrette T. Pandey A. Chinnaiyan A.M. ONCOMINE: a cancer microarray database and integrated data-mining platform.Neoplasia. 2004; 6: 1-6Crossref PubMed Google Scholar). Fgf2 plays a key role in expanding hematopoietic progenitor cell populations and is essential for hematopoietic and embryonic stem cell maintenance (30.Wilson E.L. Rifkin D.B. Kelly F. Hannocks M.J. Gabrilove J.L. Basic fibroblast growth factor stimulates myelopoiesis in long-term human bone marrow cultures.Blood. 1991; 77: 954-960Crossref PubMed Google Scholar). In myeloid progenitor cells, Fgf2 binding to Fgf-R1/R2 activates phosphoinositol 3-kinase (31.Holnthoner W. Pillinger M. Groger M. Wolff K. Ashton A.W. Albanese C. Neumeister P. Pestell R.G. Petzelbauer P. Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells.J. Biol. Chem. 2002; 277: 45847-45853Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 32.Shimizu T. Kagawa T. Inoue T. Nonaka A. Takada S. Aburatani H. Taga T. Stabilized β-catenin functions through TCF/LEF proteins and the Notch/RBP-Jκ complex to promote proliferation and suppress differentiation of neural precursor cells.Mol. Cell. Biol. 2008; 28: 7427-7441Crossref PubMed Scopus (158) Google Scholar). Phosphoinositol 3-kinase activates Akt kinase, which inhibits glycogen synthase kinase 3β. Serine/threonine phosphorylation of β-catenin by glycogen synthase kinase 3β leads to β-catenin ubiquitination and degradation. Therefore, Fgf2-induced activation of phosphoinositol 3-kinase stabilizes β-catenin and enhances β-catenin activity (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). We previously found that autocrine production of Fgf2 contributed to cytokine hypersensitivity of HoxA10-overexpressing myeloid progenitor cells in a phosphoinositol 3-kinase and β-catenin-dependent manner (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). The possibility that Fgf2 contributed to the pathogenesis of 11q23-AML was not previously explored. HoxA9 and HoxA10 have highly conserved DNA binding homeodomains, suggesting the possibility of common target genes (33.Eklund E. The role of Hox proteins in leukemogenesis. Insights into key regulatory events in hematopoiesis.Crit. Rev. Oncog. 2011; 16: 65-76Crossref PubMed Scopus (51) Google Scholar). However, HoxA9 and HoxA10 diverge outside of the homeodomain, suggesting the possibility of differential effects on some target genes. Consistent with the latter, we found that CYBB was a common target gene for HoxA10 and HoxA9 (the only previously identified common target gene) (34.Eklund E.A. Jalava A. Kakar R. Tyrosine phosphorylation decreases HoxA10 DNA-binding and transcriptional repression during IFNγ differentiation in myeloid cell lines.J. Biol. Chem. 2000; 275: 20117-20126Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 35.Lindsey S. Zhu C. Lu Y.F. Eklund E.A. HoxA10 represses transcription of the gene encoding p67PHOX in phagocytic cells.J. Immunol. 2005; 175: 5269-5279Crossref PubMed Scopus (29) Google Scholar, 36.Lindsey S. Huang W. Wang H. Horvath E. Zhu C. Eklund E.A. Activation of SHP2 protein-tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91PHOX and p67PHOX.J. Biol. Chem. 2007; 282: 2237-2249Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 37.Bei L. Lu Y. Eklund E.A. HoxA9 activates transcription of the gene encoding gp91PHOX during myeloid differentiation.J. Biol. Chem. 2005; 280: 12359-12370Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). CYBB encodes gp91phox; a rate-limiting component of the NADPH oxidase that generates H2O2/O3− during the innate immune response. We found that HoxA10 interacted with and repressed a CYBB cis element in myeloid progenitor cells (34.Eklund E.A. Jalava A. Kakar R. Tyrosine phosphorylation decreases HoxA10 DNA-binding and transcriptional repression during IFNγ differentiation in myeloid cell lines.J. Biol. Chem. 2000; 275: 20117-20126Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 36.Lindsey S. Huang W. Wang H. Horvath E. Zhu C. Eklund E.A. Activation of SHP2 protein-tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91PHOX and p67PHOX.J. Biol. Chem. 2007; 282: 2237-2249Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). During myeloid differentiation, phosphorylation of conserved tyrosine residues in the DNA binding homeodomain (HD) of HoxA10 decreased binding affinity for CYBB (34.Eklund E.A. Jalava A. Kakar R. Tyrosine phosphorylation decreases HoxA10 DNA-binding and transcriptional repression during IFNγ differentiation in myeloid cell lines.J. Biol. Chem. 2000; 275: 20117-20126Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 36.Lindsey S. Huang W. Wang H. Horvath E. Zhu C. Eklund E.A. Activation of SHP2 protein-tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91PHOX and p67PHOX.J. Biol. Chem. 2007; 282: 2237-2249Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). HoxA9 activated CYBB transcription through the same cis element, but in this case phosphorylation of the conserved HD tyrosine residues of HoxA9 increased CYBB binding affinity during differentiation (37.Bei L. Lu Y. Eklund E.A. HoxA9 activates transcription of the gene encoding gp91PHOX during myeloid differentiation.J. Biol. Chem. 2005; 280: 12359-12370Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). These studies identified an antagonistic role for HoxA9 and HoxA10 during myeloid differentiation. This was consistent with previous studies indicating that HoxA10 was involved in a differentiation block in AML, but HoxA9 conferred a myeloid phenotype upon leukemia cells (13.Calvo K.R. Sykes D.B. Pasillas M. Kamps M.P. Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression.Mol. Cell. Biol. 2000; 20: 3274-3285Crossref PubMed Scopus (117) Google Scholar, 18.Wang H. Lindsey S. Konieczna I. Bei L. Horvath E. Huang W. Saberwal G. Eklund E.A. Constitutively active SHP2 cooperates with HoxA10 overexpression to induce acute myeloid leukemia.J. Biol. Chem. 2009; 284: 2549-2567Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). However, in the current study we found that HoxA9 and HoxA10 activated common cis elements in the FGF2 promoter in myeloid progenitor cells and throughout myeloid differentiation. Expression of the leukemia-associated MLL fusion protein Mll-Ell also activated these two FGF2 cis elements in a HoxA9- and HoxA10-dependent manner. This resulted in autocrine production of Fgf2 by Mll-Ell-expressing myeloid progenitor cells and Fgf2-dependent cytokine hypersensitivity. This is a previously un-described and therapeutically targetable mechanism for MLL fusion proteins to influence expansion of myeloid progenitor cells. The cDNA for human HoxA10 was obtained from C. Largman (University of California, San Francisco) (38.Lowney P. Corral J. Detmer K. LeBeau M.M. Deaven L. Lawrence H.J. Largman C. A human Hox 1 homeobox gene exhibits myeloid-specific expression of alternative transcripts in human hematopoietic cells.Nucleic Acids Res. 1991; 19: 3443-3449Crossref PubMed Scopus (67) Google Scholar). The HoxA9 cDNA was generated by reverse transcription and PCR from U937 cells as described (37.Bei L. Lu Y. Eklund E.A. HoxA9 activates transcription of the gene encoding gp91PHOX during myeloid differentiation.J. Biol. Chem. 2005; 280: 12359-12370Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). These cDNAs were subcloned into the mammalian expression vector pcDNAamp (Invitrogen) and the murine retroviral vector pMSCVpuro (Clontech, Mountain View, CA), as described (21.Wang H. Lu Y. Huang W. Papoutsakis E.T. Fuhrken P. Eklund E.A. HoxA10 activates transcription of the gene encoding mitogen-activated protein kinase phosphatase 2 (Mkp2) in myeloid cells.J. Biol. Chem. 2007; 282: 16164-16176Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 22.Bei L. Lu Y. Bellis S.L. Zhou W. Horvath E. Eklund E.A. Identification of a HoxA10 activation domain necessary for transcription of the gene encoding β3 integrin during myeloid differentiation.J. Biol. Chem. 2007; 282: 16846-16859Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). A vector with the Mll-Ell fusion protein was obtained from D. E. Zhang (University of California, San Diego, CA). HoxA10- and HoxA9-specific shRNA and scrambled control sequences were designed using the Promega website (Promega, Madison, WI) and subcloned into the pLKO.1puro vector (from Dr. Kathy Rundell, Northwestern University, Chicago). Several sequences were tested, and the most efficient were combined. The FGF2 5′-flank was obtained from the genomic DNA of U937 cells by PCR. The sequence was compared with the published FGF2 5′-flank sequence (ENSEMBL database), and promoter fragments were subcloned into the pGL3-basic reporter vector (Promega) as described (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Other constructs were generated with mutation of identified Hox binding sites in the FGF2 promoter. Reporter constructs were also generated using the pGL3-promoter vector (with a minimal promoter and reporter) and three copies of the proximal (−287 to −266 bp) or distal (−448 to −425 bp) Hox binding cis elements from the FGF2 promoter as described (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Oligonucleotides were custom-synthesized by MWG Biotech (Piedmont, NC). These oligonucleotides represent Hox consensus sequences from the FGF2 promoter; −287 to −266 bp (5′-GAGAAAGTTGAGTTTAAACTTTTA-3′), −448 to −425 bp (5′-AATTTTAAAGTTTATGCCCCATT-3′), or Hox-consensus mutants of these sequences (26.Shah C.A. Bei L. Wang H. Platanias L.C. Eklund E.A. HoxA10 protein regulates transcription of gene encoding fibroblast growth factor 2 (FGF2) in myeloid cells.J. Biol. Chem. 2012; 287: 18230-18248Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). The human myelomonocytic leukemia cell line U937 (39.Larrick J.W. Fischer D.G. Anderson S.J. Koren H.S. Characterization of a human macrophage-like cell line stimulated in vitro. A model of macrophage functions.J. Immunol. 1980; 125: 6-12Crossref PubMed Google Scholar) was obtained from A. Kraft (Hollings Cancer Center, Medical University of South Carolina, Charleston, SC). Cells were maintained and differentiated (with retinoic acid (RA) and dimethylformamide (DMF)) as described (39.Larrick J.W. Fischer D.G. Anderson S.J. Koren H.S. Characterization of a human macrophage-like cell line stimulated in vitro. A model of macrophage functions.J. Immunol. 1980; 125: 6-12Crossref PubMed Google Scholar)." @default.
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• W1982901636 title "The Leukemia-associated Mll-Ell Oncoprotein Induces Fibroblast Growth Factor 2 (Fgf2)-dependent Cytokine Hypersensitivity in Myeloid Progenitor Cells" @default.
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