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Chronic Myeloproliferative Neoplasias

Deletions of the transcription factor Ikaros in myeloproliferative neoplasms

Leukemia volume 24, pages 1290–1298 (2010)Cite this article

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Abstract

Transformation to acute leukemia is a major complication of myeloproliferative neoplasms (MPNs), however, the genetic changes leading to transformation remain largely unknown. We screened nine patients with post-MPN leukemia for chromosomal aberrations using microarray karyotyping. Deletions on the short arm of chromosome 7 (del7p) emerged as a recurrent defect. We mapped the common deleted region to the IKZF1 gene, which encodes the transcription factor Ikaros. We further examined the frequency of IKZF1 deletions in a total of 29 post-MPN leukemia and 526 MPN patients without transformation and observed a strong association of IKZF1 deletions with post-MPN leukemia in two independent cohorts. Patients with IKZF1 loss showed complex karyotypes, and del7p was a late event in the genetic evolution of the MPN clone. IKZF1 deletions were observed in both undifferentiated and differentiated myeloid cell types, indicating that IKZF1 loss does not cause differentiation arrest but rather renders progenitors susceptible to transformation, most likely through chromosomal instability. Induced Ikzf1 haploinsufficiency in primary murine progenitors resulted in elevated Stat5 phosphorylation and increased cytokine-dependent growth, suggesting that reduced expression of IKZF1 is sufficient to perturb growth regulation. Thus, IKZF1 loss is an important step in the leukemic transformation of a subpopulation of MPN patients.

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Acknowledgements

The study was supported by funding from the Austrian Academy of Sciences, the Austrian Science Fund (FWF, P20033-B11) and the MPD Foundation, as well as from AIRC (Associazione Italiana per la Ricerca sul Cancro, Milan), Fondazione Cariplo (Milan), PRIN-MIUR (Rome) and Alleanza Contro il Cancro (Rome), all in Italy. We thank Sebastian Nijman, Markus Muellner and Nils Craig-Mueller for technical assistance and advice and Helen Pickersgill for helpful comments on the paper.

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Authors and Affiliations

  1. Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    R Jäger, T Berg, A Harutyunyan, T Klampfl, D Olcaydu & R Kralovics

  2. Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria

    H Gisslinger, B Gisslinger & R Kralovics

  3. Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy

    F Passamonti, E Rumi, D Pietra & M Cazzola

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  1. R Jäger
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Correspondence to R Kralovics.

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Jäger, R., Gisslinger, H., Passamonti, F. et al. Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia 24, 1290–1298 (2010). https://doi.org/10.1038/leu.2010.99

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