Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (2023)

Abstract

The association between acute myeloid leukaemia (AML) and the aberrant expression of Hoxa9 is evidenced by (1) proviral activation of Hoxa9 and Meis1 in BXH-2 murine AML, (2) formation of the chimeric Nup98-HoxA9 transactivator protein as a consequence of the t(7;11) translocation in human AML, and (3) the strong expression of HoxA9 and Meis1 in human AML. In mouse models, enforced retroviral expression of Hoxa9 alone in marrow is not sufficient to cause rapid AML, while co-expression of Meis1 and Hoxa9 induces rapid AML. In contrast, retroviral expression of Nup98-HoxA9 is sufficient to cause rapid AML in the absence of enforced Meis1 expression. Previously, we demonstrated that Hoxa9 could block the differentiation of murine marrow progenitors cultured in granulocyte-macrophage colony-simulating factor (GM–CSF). These progenitors lacked Meis1 expression, could not proliferate in stem cell factor (SCF), but could differentiate into neutrophils when switched into granulocyte colony-simulating factor (G-CSF). Ectopic expression of Meis1 in these Hoxa9 cells suppressed their G-CSF-induced differentiation, permitted proliferation in SCF, and therein offered a potential explanation of cooperative function. Because Meis1 binds N-terminal Hoxa9 sequences that are replaced by Nup98, we hypothesized that Nup98-HoxA9 might consolidate the biochemical functions of both Hoxa9 and Meis1 on target gene promoters and might evoke their same lymphokine-responsive profile in immortalized progenitors. Here we report that Nup98-HoxA9, indeed mimicks Hoxa9 plus Meis1 coexpression – it immortalizes myeloid progenitors, prevents differentiation in response to GM–CSF, IL-3, G-CSF, and permits proliferation in SCF. Unexpectedly, however, Nup98-Hoxa9 also enforced strong transcription of the cellular Hoxa9, Hoxa7 and Meis1 genes at levels similar to those found in mouse AML's generated by proviral activation of Hoxa9 and Meis1. Using Hoxa9−/− marrow, we demonstrate that expression of Hoxa9 is not required for myeloid immortalization by Nup98-HoxA9. Rapid leukaemogenesis by Nup98-HoxA9 may therefore result from both the intrinsic functions of Nup98-HoxA9, as well as of those of coexpressed HOX and MEIS1 genes.

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Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (1)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (2)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (3)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (4)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (5)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (6)
Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 (7)

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Acknowledgements

MP Kamps is a scholar of the Leukemia Society of America. KR Calvo is supported by NIH Training Grant CA77109-01. DB Sykes is supported by a grant from the Department of Defense. Antisera against the mouse macrophage acetyl-LDL scavenger receptor was a kind gift from Dr Christopher Glass. We thank Dr Jeffrey Lawrence for the kind gift of Hoxa9−/− mice and Dr Mario Capecchi for permitting us to use this strain. We thank Dennis J Young in the UCSD Cancer Center's Flow Cytometry Shared Resource for his flow cytometry expertise and Dr James Feramisco for assistance in deconvolution microscopy. DNA sequencing was performed by the Molecular Pathology Shared Resource, UCSD Cancer Center, which is funded in part by NCI Cancer Center Support Grant #5P0CA23100-16. This work was supported by NIH grant CA56876.

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  1. Department of Pathology 9500 Gilman Drive, University of California School of Medicine, La Jolla, 92093-0612, California, CA, USA

    Katherine R Calvo,David B Sykes,Martina P Pasillas&Mark P Kamps

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Calvo, K., Sykes, D., Pasillas, M. et al. Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1. Oncogene 21, 4247–4256 (2002). https://doi.org/10.1038/sj.onc.1205516

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Keywords

  • Hoxa9
  • Nup98-HoxA9
  • Meis1
  • leukaemia
  • AML

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