title: Down-regulation of homeobox genes MEIS1 and HOXA in MLL-rearranged acute leukemia impairs engraftment and reduces proliferation.
abstract: Rearrangements of the MLL (ALL1) gene are very common in acute infant and therapy-associated leukemias. The rearrangements underlie the generation of MLL fusion proteins acting as potent oncogenes. Several most consistently up-regulated targets of MLL fusions, MEIS1, HOXA7, HOXA9, and HOXA10 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-augmented 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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Kira
authors.initials: K
authors.lastname: Orlovsky
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Tanya
authors.initials: T
authors.lastname: Rozovskaia
authors.forename: Elias
authors.initials: E
authors.lastname: Shezen
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Hatice Gulcin
authors.initials: HG
authors.lastname: Ozer
authors.forename: Letizia
authors.initials: L
authors.lastname: Carramusa
authors.forename: Abraham
authors.initials: A
authors.lastname: Avigdor
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Arthur
authors.initials: A
authors.lastname: Buchberg
authors.forename: Alex
authors.initials: A
authors.lastname: Mazo
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Corey
authors.initials: C
authors.lastname: Largman
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
authors.forename: Eli
authors.initials: E
authors.lastname: Canaani
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D015321:Gene Rearrangement; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C113855:MLL-AF4 fusion protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; C088144:HoxA protein; D011495:Histone-Lysine N-Methyltransferase