Down-regulation of homeobox genes MEIS1 and HOXA in MLL-rearranged acute leukemia impairs engraftment and reduces proliferation

Kira Orlovsky, Alexander Kalinkovich, Tanya Rozovskaia, Elias Shezen, Tomer Itkin, Hansjuerg Alder, Hatice Gulcin Ozer, Letizia Carramusa, Abraham Avigdor, Stefano Volinia, Arthur Buchberg, Alex Mazo, Orit Kollet, Corey Largman, Carlo M. Croce, Tatsuya Nakamura, Tsvee Lapidot, Eli Canaani

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

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.

Original languageEnglish
Pages (from-to)7956-7961
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number19
DOIs
StatePublished - 10 May 2011
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteP01CA129242

    Keywords

    • Bone marrow colonization of leukemic cells
    • Leukemic cells' migration

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