Functional Crosstalk between Bmi1 and MLL/Hoxa9 Axis in Establishment of Normal Hematopoietic and Leukemic Stem Cells

• Published in: Cell stem cell 2011-06, Vol.8 (6), p.649-662
• Main Authors: Smith, Lan-Lan, Yeung, Jenny, Zeisig, Bernd B., Popov, Nikolay, Huijbers, Ivo, Barnes, Josephine, Wilson, Amanda J., Taskesen, Erdogan, Delwel, Ruud, Gil, Jesús, Van Lohuizen, Maarten, So, Chi Wai Eric
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Coculture Techniques; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular and cellular biology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nuclear Proteins - deficiency; Nuclear Proteins - metabolism; Oncogene Proteins, Fusion - metabolism; Polycomb Repressive Complex 1; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - metabolism; Repressor Proteins - deficiency; Repressor Proteins - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2011.05.004

Bmi1 is required for efficient self-renewal of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). In this study, we investigated whether leukemia-associated fusion proteins, which differ in their ability to activate Hox expression, could initiate leukemia in the absence of Bmi1. AML1-ETO and PLZF-RARα, which do not activate Hox, triggered senescence in Bmi1 −/− cells. In contrast, MLL-AF9, which drives expression of Hoxa7 and Hoxa9, readily transformed Bmi1 −/− cells. MLL-AF9 could not initiate leukemia in Bmi1 −/−Hoxa9 −/− mice, which have further compromised HSC functions. But either gene could restore the ability of MLL-AF9 to establish LSCs in the double null background. As reported for Bmi1, Hoxa9 regulates expression of p16 Ink4a/p19 ARF locus and could overcome senescence induced by AML1-ETO. Together, these results reveal an important functional interplay between MLL/Hox and Bmi1 in regulating cellular senescence for LSC development, suggesting that a synergistic targeting of both molecules is required to eradicate a broader spectrum of LSCs. [Display omitted] ► MLL-AF9, but not AML1-ETO, is capable of establishing LSCs in the absence of Bmi1 ► Ablation of Hoxa9 abolishes Bmi1-independent establishment of MLL LSCs in Bmi1 −/− cells ► Hoxa9 suppresses expression of p16 Ink4a and p19 Arf and senescence ► Synergistic targeting of Bmi1 and Hox pathways is required for certain LSCs