{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:20:45Z","timestamp":1789392045376,"version":"build-2803163510"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"19","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,5,10]]},"abstract":"<jats:p>\n                    Rearrangements of the\n                    <jats:italic>MLL (ALL1)<\/jats:italic>\n                    gene are very common in acute infant and therapy-associated leukemias. The rearrangements underlie the generation of\n                    <jats:italic>MLL<\/jats:italic>\n                    fusion proteins acting as potent oncogenes. Several most consistently up-regulated targets of MLL fusions,\n                    <jats:italic>MEIS1<\/jats:italic>\n                    ,\n                    <jats:italic>HOXA7, HOXA9,<\/jats:italic>\n                    and\n                    <jats:italic>HOXA10<\/jats:italic>\n                    are functionally related and have been implicated in other types of leukemias. Each of the four genes was knocked down separately in the human precursor B-cell leukemic line RS4;11 expressing MLL-AF4. The mutant and control cells were compared for engraftment in NOD\/SCID mice. Engraftment of all mutants into the bone marrow (BM) was impaired. Although homing was similar, colonization by the knockdown cells was slowed. Initially, both types of cells were confined to the trabecular area; this was followed by a rapid spread of the WT cells to the compact bone area, contrasted with a significantly slower process for the mutants. In vitro and in vivo BrdU incorporation experiments indicated reduced proliferation of the mutant cells. In addition, the CXCR4\/SDF-1 axis was hampered, as evidenced by reduced migration toward an SDF-1 gradient and loss of SDF-1\u2013augmented proliferation in culture. The very similar phenotype shared by all mutant lines implies that all four genes are involved and required for expansion of MLL-AF4 associated leukemic cells in mice, and down-regulation of any of them is not compensated by the others.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1103154108","type":"journal-article","created":{"date-parts":[[2011,4,25]],"date-time":"2011-04-25T23:05:55Z","timestamp":1303772755000},"page":"7956-7961","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":56,"title":["Down-regulation of homeobox genes\n                    <i>MEIS1<\/i>\n                    and\n                    <i>HOXA<\/i>\n                    in\n                    <i>MLL<\/i>\n                    -rearranged acute leukemia impairs engraftment and reduces proliferation"],"prefix":"10.1073","volume":"108","author":[{"given":"Kira","family":"Orlovsky","sequence":"first","affiliation":[{"name":"Departments of aMolecular Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kalinkovich","sequence":"additional","affiliation":[{"name":"Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel; Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Rozovskaia","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Shezen","sequence":"additional","affiliation":[{"name":"Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel; Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomer","family":"Itkin","sequence":"additional","affiliation":[{"name":"Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel; Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansjuerg","family":"Alder","sequence":"additional","affiliation":[{"name":"Molecular Virology, Immunology and Medical Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatice Gulcin","family":"Ozer","sequence":"additional","affiliation":[{"name":"Biomedical Informatics, Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"Carramusa","sequence":"additional","affiliation":[{"name":"Departments of aMolecular Cell Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Avigdor","sequence":"additional","affiliation":[{"name":"Hematology Division, Sheba Medical Center, Tel-Hashomer, 52621, Israel;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Volinia","sequence":"additional","affiliation":[{"name":"Molecular Virology, Immunology and Medical Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Buchberg","sequence":"additional","affiliation":[{"name":"Departments of fMicrobiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Mazo","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orit","family":"Kollet","sequence":"additional","affiliation":[{"name":"Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel; Departments of"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Largman","sequence":"additional","affiliation":[{"name":"Veteran Affairs Medical Center, San Francisco, CA 94121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[{"name":"Molecular Virology, Immunology and Medical Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Molecular Virology, Immunology and Medical Genetics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsvee","family":"Lapidot","sequence":"additional","affiliation":[{"name":"Immunology, Weizmann Institute of Science, Rehovot, 76100 Israel; 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