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MicroRNA-155 induces AML in combination with the loss of C/EBPA in mice

Leukemia volume 30, pages 2238–2241 (2016)Cite this article

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MicroRNAs (miRNAs) are frequently deregulated in human cancer, including acute myeloid leukemia (AML).1 Recent studies have shown that miRNA miR-155 is an oncogenic miRNA (oncomiR). For instance, EÎĽ/VH-miR-155-transgenic mice, that express miR-155 from the immunoglobulin heavy chain promoter, develop acute lymphoblastic leukemia (ALL).2 Mutations in FMS-related tyrosine kinase 3 (FLT3) are present in ~30% of AML patients.3 The most common mutations are in-frame internal tandem duplications (ITDs) in the juxtamembrane domain of the receptor.3 FLT3-ITDs cause autophosphorylation and ligand-independent activation of the FLT3 receptor, and downstream signaling pathways, including janus kinase (JAK)/STAT, v-akt murine thymoma viral oncogene homolog 1 and extracellular signal-regulated kinase (ERK), and induce miR-155 expression through the activation of nuclear factor-ÎşB (p65), and signal transducer and activator of transcription 5 (STAT5).4, 5, 6 Similar to FLT3-ITD transgenic mice, mice transplanted with hematopoietic stem and progenitor cells (HSPCs) ectopically expressing miR-155 develop a myeloproliferative neoplasm, but do not progress to ALL or AML.7, 8 Computational analyses and studies in FLT3-ITD-positive cell lines suggest that miR-155 alters hematopoiesis via downregulation of SPI1 and C/EBPB.9 Hence, it remained largely unclear how miR-155 upregulation contributes to the development of FLT3-ITD AML. Here, we show that complete loss of C/EBPA activity in myeloid progenitors is a critical step in miR-155-induced AML development, which does not depend on additional signaling defects projected by the FLT3-ITD mutants.

FLT3-ITD causes both a reduced expression and activity of C/EBPA, the latter by constitutive activation of the ERK1/2 pathway and CDK1-mediated phosphorylation of C/EBPA serine 21.12, 13 In full agreement, we found that the expression of CSF3R, which is a well-established target of C/EBPA, is significantly downregulated in bFLT3-ITD compared with FLT3-WT (P<0.05); (Supplementary Table 1). Dominant negative mutations in C/EBPA, epigenetic silencing and functional inactivation have been implicated in the pathogenesis of AML in a vast majority of patients.14, 15 Approximately 6.5% of AML patients harbor either dominant negative mutations in C/EBPA or lack expression due to DNA methylation16, 17 (Supplementary Figure 1). In these cases, FLT3-ITDs are significantly underrepresented relative to the total AML population (8.3% versus ~28%, respectively, P=0.01, Fisher’s exact test), supporting the idea that FLT3-ITDs exert a major negative regulatory effect on C/EBPA function and are therefore largely mutually exclusive with C/EBPA DNA methylation or silencing. Together, these data indicate that the inactivation of C/EBPA is a major event in FLT3-ITD leukemia. Because loss of C/EBPA in HSPCs causes a block in myeloid differentiation18 and enhanced expression of miR-155 in hematopoietic stem cells results in a myeloproliferative disorder,7, 8 we reasoned that these two events in cooperation suffice to cause AML, that is independent of additional signaling aberrations associated with FLT3-ITD.

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Acknowledgements

We thank Dr Daniel G Tenen for the Floxed (fl) C/ebpa mice (C/ebpafl/fl).18 We thank Dr Elwin Rombouts and Nicole GJA van Boxtel for the technical assistance. This work was supported by a grant from the Dutch Cancer Society (KWF) EMCR 2009-4482.

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Authors and Affiliations

  1. Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, The Netherlands

    M F Alemdehy, H W J de Looper, F G Kavelaars, M A Sanders, R Hoogenboezem, B Löwenberg, P J M Valk, I P Touw & S J Erkeland

  2. Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    M F Alemdehy

  3. Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands

    S J Erkeland

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  1. M F Alemdehy
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Correspondence to S J Erkeland.

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Alemdehy, M., de Looper, H., Kavelaars, F. et al. MicroRNA-155 induces AML in combination with the loss of C/EBPA in mice. Leukemia 30, 2238–2241 (2016). https://doi.org/10.1038/leu.2016.171

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