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Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia

Leukemia volume 24, pages 1200–1204 (2010)Cite this article

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IKAROS is a chromatin-remodeling and sequence-specific transcription factor encoded by the IKZF1 gene that is involved in a number of developmental processes in hematopoiesis. In particular, IKAROS is essential for the specification of the lymphoid lineages from myeloid/lymphoid multipotent progenitors, is involved in the differentiation of pro-B cells into pre-B cells and, together with the related IKAROS family member Aiolos, downregulates pre-BCR function (for a review, see Nutt and Kee1). Over the past 10 years, reverse transcription–PCR studies have reported the expression of short IKAROS isoforms in acute lymphoblastic leukemia (ALL) patients at diagnosis, with higher prevalence in BCR-ABL-associated B-ALL.2 These short isoforms encode IKAROS proteins that include only two out of the four central zinc fingers responsible for their specific binding to DNA while keeping intact the C-terminal zinc fingers involved in their oligomerization with DNA-binding-competent isoforms of IKAROS and other IKAROS family members. Thus, these short isoforms can function as dominant-negative (DN) mutants of wild-type (wt) IKAROS and IKAROS family members. Recently, comprehensive genome-wide SNP array analyses of DNA copy number alterations in ALL showed the frequent monoallelic deletion of all or part of IKZF1, the latter situation often linked to the expression of DN IKAROS isoforms in >75% of pediatric and >90% of adult BCR-ABL B-ALL and lymphoid blast crisis chronic myeloid leukemia (CML) patients.3 These data suggest that impaired function of IKAROS itself, and possibly of other members of the IKAROS family, could be instrumental in BCR-ABL-induced B-ALL progression and poor clinical outcome.4

Western blot analyses showed that sorted BCR-ABL+/0; IK+/+ leukemic cells expressed the DNA-binding-competent IK1 and IK2 IKAROS isoforms at levels indistinguishable from that of normal B-cell progenitors, with no evidence for expression of short IKAROS isoforms (Figure 1d; Supplementary Figure 1). This shows that the natural course of leukemia progression in BCR-ABL+/0; IK+/+ mice is not associated with impaired expression of IKAROS or with induction of the expression of DN IKAROS isoforms. BCR-ABL+/0; IKL/+ leukemic cells showed the expected 50% decrease in expression in IK1/2 and the expression at low levels of the N-terminally shortened IK1/2* polypeptides encoded by the hypomorphic IKAROS allele,6 but no expression of DN IKAROS isoforms. This indicates that the experimentally imposed impaired function of IKZF1 does not favor the inactivation of the remaining wt allele during leukemia progression. Hemizygous deletion of PAX5 is observed in about 50% of BCR-ABL-positive B-ALL patients.3 Western blot analysis failed to detect any change in Pax5 expression in leukemic cells obtained from our BCR-ABL transgenic cohorts irrespective of their IKAROS status, as compared with normal B-cell progenitors (Figure 1d). We conclude from these experiments that loss of a single wt IKZF1 allele is sufficient to cooperate strongly with BCR-ABL in B-cell leukemogenesis.

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Acknowledgements

We thank Meinrad Busslinger for discussions and the gift of anti-PAX5 antibody; Zofia Maciorowski, Annick Viguier and Niraja Shah for help with FACS analyses ; Philippe Hupé, Philippe La Rosa and Stéphane Liva for VAMP analyses of CGH array data ; Josiane Ropers for assistance in mouse husbandry; and Maryvonne Williame for help with mouse genotyping. This work was supported by funds from Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Institut National du Cancer (INCA, Grant no. PLBIO08-092), Ligue Nationale contre le Cancer (JG and SC/PK are Equipe labelisée Ligue contre le Cancer). SM was supported by a post-doctoral fellowship from the Ligue Contre le Cancer and CV by pre-doctoral fellowships from the Ministère de l’Education Nationale and Association contre le Cancer (ARC). Research in CC laboratory was supported by FEDER (FIS PI080164), CSIC and Junta de Castilla y Leon (SA060A09 and proyecto Biomedicina).

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Author notes

  1. C Virely and S Moulin: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche, Institut Curie, Centre Universitaire Bat 110, Orsay, France

    C Virely, S Moulin, C Lasgi & J Ghysdael

  2. CNRS UMR 3306, Centre Universitaire Bat 110, Orsay, France

    C Virely, S Moulin, C Lasgi & J Ghysdael

  3. INSERM U1005, Centre Universitaire Bat 110, Orsay, France

    C Virely, S Moulin, C Lasgi & J Ghysdael

  4. Ecole Doctorale B2T, Université Paris–Diderot, Paris, France

    C Virely

  5. Area de Desarrollo y Diferenciacion, Centro de Biologia Molecular ‘Severo Ochoa’, CSIC–Universidad Autonoma de Madrid, Madrid, Spain

    C Cobaleda

  6. INSERM U944, Institut Universitaire d’Hématologie, Hopital Saint Louis, Paris, France

    A Alberdi, J Soulier & F Sigaux

  7. Institut Universitaire d’Hématologie, Université Paris–Diderot, Paris, France

    A Alberdi, J Soulier & F Sigaux

  8. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    S Chan & P Kastner

  9. INSERM U 964, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    S Chan & P Kastner

  10. CNRS UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    S Chan & P Kastner

  11. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France

    S Chan & P Kastner

  12. Faculté de Médecine, Université de Strasbourg, Strasbourg, France

    P Kastner

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  1. C Virely
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Correspondence to J Ghysdael.

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Virely, C., Moulin, S., Cobaleda, C. et al. Haploinsufficiency of the IKZF1 (IKAROS) tumor suppressor gene cooperates with BCR-ABL in a transgenic model of acute lymphoblastic leukemia. Leukemia 24, 1200–1204 (2010). https://doi.org/10.1038/leu.2010.63

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