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Transcriptional control and signal transduction, cell cycle

Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3+-mediated leukemic phenotype

Leukemia volume 30, pages 1725–1733 (2016)Cite this article

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Abstract

Mutations that activate FMS-like tyrosine kinase 3 (FLT3) are frequent occurrences in acute myeloid leukemia. Two distinct types of mutations have been described: internal duplication of the juxtamembranous domain (ITD) and point mutations of the tyrosine kinase domain (TKD). Although both mutations lead to constitutive FLT3 signaling, only FLT3-ITD strongly activates signal transducer and activator of transcription 5 (STAT5). In a murine transplantation model, FLT3-ITD induces a myeloproliferative neoplasm, whereas FLT3-TKD leads to a lymphoid malignancy with significantly longer latency. Here we report that the presence of STAT5 is critical for the development of a myeloproliferative disease by FLT3-ITD in mice. Deletion of Stat5 in FLT3-ITD-induced leukemogenesis leads not only to a significantly longer survival (82 vs 27 days) of the diseased mice, but also to an immunophenotype switch with expansion of the lymphoid cell compartment. Interestingly, we were able to show differential STAT5 activation in FLT3-ITD+ myeloid and lymphoid murine progenitors. STAT5 target genes such as Oncostatin M were highly expressed in FLT3-ITD+ myeloid but not in FLT3-ITD+ lymphoid progenitor cells. Strikingly, FLT3-TKD expression in combination with Oncostatin M is sufficient to reverse the phenotype to a myeloproliferative disease in FLT3-TKD mice. Thus, lineage-specific STAT5 activation in hematopoietic progenitor cells predicts the FLT3+-mediated leukemic phenotype in mice.

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Acknowledgements

We thank M Follo for help with FACS sorting and G Schäfer for technical assistance. This work was supported by a DFG grant (FOR 2033 to JD and TAM). LH was supported by the Intramural Research Program (IRP) of the National Institutes of Diabetes, Digestive and Kidney Disease, NIH (Bethesda, MD, USA). ALI was supported by a Research grant from University Clinic Freiburg and from the government Baden-Württemberg (BSL).

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Author notes

  1. T A Müller and R Grundler: These authors contributed equally to this work.

  2. A L Illert and J Duyster: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany

    T A Müller, A L Illert & J Duyster

  2. 3rd Department of Internal Medicine, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany

    R Grundler & R Istvanffy

  3. Department of Pathology, Klinikum Rechts der Isar der Technischen Universität München, Munich, Germany

    M Rudelius

  4. Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany

    M Rudelius

  5. NIDDK, National Institutes of Health, Bethesda, MD, USA

    L Hennighausen

  6. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    A L Illert & J Duyster

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  1. T A Müller
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Correspondence to A L Illert or J Duyster.

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Müller, T., Grundler, R., Istvanffy, R. et al. Lineage-specific STAT5 target gene activation in hematopoietic progenitor cells predicts the FLT3+-mediated leukemic phenotype. Leukemia 30, 1725–1733 (2016). https://doi.org/10.1038/leu.2016.72

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