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The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development

Leukemia volume 24, pages 1227–1230 (2010)Cite this article

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The serum response transcription factor (Srf) controls developmental programs and proliferation, differentiation, cellular shape and cytoskeleton organization. Its activity is regulated through the mitogen-activated protein kinase pathway (MAPK)/Erk pathway and the GTPases Rho/mDia/actin pathway, allowing integration of extracellular mitogenic signals with changes in actin cytoskeleton. The Srf co-activators myocardin-related transcription factors (Mrtfs) assist Srf in the expression of genes linked to actin cytoskeleton dynamics. Among Mrtfs, the megakaryocytic acute leukemia (MAL) (also known as Mrtf-A and megakaryoblastic leukemia-1) is an actin-binding protein whose nuclear accumulation is controlled by the actin treadmilling cycle.1, 2 The human MAL gene is fused to the OTT/RBM15 gene in acute megakaryoblastic leukemia (AMKL)3, 4 and a contribution of Mal activity to the late steps of murine and human megakaryopoiesis has been reported.5, 6 Although the lack of Srf results in major cellular defects and embryonic lethality (reviewed in Miano et al.7), Mal germ line deficiency results in a limited myoepithelial cells phenotype8, 9 probably because of the redundancies of Mrtf proteins.

Although the human MAL gene is specifically involved in the pathogenesis of a pediatric AMKL through its involvement in the t(1;22)(p13;q13) chromosomic translocation, Mal ablation does not affect on most primitive hematopoietic cells development, nor on MEP, CMP and GMP compartments (Supplementary Figure 4). This contrasts with the severe phenotypes that frequently afflict hematopoietic stem cells and/or their progenitors on invalidation of leukemia-associated transcriptional regulators.19 In addition, the Mk-restricted defects observed in Mal-deficient adult hematopoiesis contrast with the dramatic effects observed in adult animals on Srf inactivation (Ragu et al. submitted). These discrepancies could be explained by functional redundancies between Mrtf factors in the other hematopoietic cells and/or by the presence of a functional ternary complex factor/Srf pathway activated by the MAPK/Erk signalling, in Mal-null animals.

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Acknowledgements

We thank L Gilles for technical advices. J Di Santo (Institut Pasteur, Paris, France) provided the Mx1-Cre mice. Funding from INSERM, ARC, LNCC (équipes labelisées OAB and WV) and INCa supported this work. CR was funded by a fellowship from the FRM and the SFH. GE was funded by an ARC/INCa grant. SB is funded by a fellowship from the INCa.

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Author notes

  1. C Ragu and S Boukour: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U985, Institut Gustave Roussy, Villejuif, France

    C Ragu, G Elain, O A Bernard & V Penard-Lacronique

  2. Université Paris Descartes, 12 rue de l'Ecole de médecine, Paris, France

    C Ragu, G Elain, D Daegelen, O A Bernard & V Penard-Lacronique

  3. INSERM U1009, Institut Gustave Roussy, Villejuif, France

    S Boukour, O Wagner-Ballon, H Raslova, N Debili & W Vainchenker

  4. Université Paris Sud 11, Orsay, France

    S Boukour, O Wagner-Ballon, H Raslova, N Debili & W Vainchenker

  5. University of Texas Southwestern Medical Center, Dallas, TX, USA

    E N Olson

  6. INSERM, U567, Paris, France

    D Daegelen

  7. Centre National de la Recherche Scientifique (CNRS), UMR8104, Paris, France

    D Daegelen

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Correspondence to V Penard-Lacronique.

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Ragu, C., Boukour, S., Elain, G. et al. The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development. Leukemia 24, 1227–1230 (2010). https://doi.org/10.1038/leu.2010.80

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