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The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB–MYH11-positive acute myeloid leukemia

Leukemia volume 24, pages 857–859 (2010)Cite this article

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NDE1 codes for a 355 aa protein that physically interacts with LIS1. Inherited LIS1 mutations abrogate NDE1 interactions and cause Miller–Dieker syndrome, which is characterized by a profound neuronal migratory disturbance known as lissencephaly or smooth brain. NDE1 and LIS1 are both required for mitotic progression of cortical progenitors in the developing brain. These proteins regulate neuronal progenitor self-renewal and differentiation during initial phases of cortical development. Loss of NDE1/LIS1 function impairs asymmetric cell division resulting in increased neurogenic division with overproduction of neurons.5 Recently, a fusion of NDE1 with PDGFRb (platelet-derived growth factor receptor-β) was described in a patient with chronic myelomonocytic leukemia.6 As the break point in NDE1 occurred in intron 5, it did not affect the MYH11 gene. Interestingly, the NDE1–PDGFRb fusion protein was found to be constitutively phosphorylated, possibly as a consequence of homodimerization through the NDE1 moiety. Functional studies showed that NDE1–PDFGRb transformed Ba/F3 cells to interleukin-3-independent growth that could be inhibited by the tyrosine kinase inhibitor imatinib mesylate.6 Treatment of the NDE1–PDFGRb-positive patient with imatinib resulted in a complete hematological response that was accompanied with disappearance of NDE1–PDGFRb-positive cells as shown by karyotyping and fluorescence in situ hybridization analysis.7 These data clearly define a role for NDE1 in malignant transformation in CBFB–MYH11-negative leukemia.

Although it has been well established that CBFB–MYH11 contributes to leukemia development, additional mutations are required for complete malignant transformation. At present, it is unclear whether disruption of one NDE1 allele contributes to malignant transformation. If so, this might explain why genomic break points cluster downstream in MYH11, as these also disrupt NDE1. In patients with upstream MYH11 break points, NDE1 is not disrupted and other mutations may be needed to cause full-blown leukemia. It will therefore be interesting to determine whether inv(16) cases with downstream genomic MYH11 break points have a different prognosis compared with those with upstream break points. We conclude that the role of NDE1 in controlling neuronal stem cell division, the contribution of NDE1–PDGFRb to leukemia development and the findings reported here warrant further studies to determine the role of NDE1 in normal and malignant hematopoiesis.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Laboratory of Hematology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    B A Van der Reijden, M Massop & J H Jansen

  2. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    A Simons

  3. Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    T de Witte

  4. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    M Breuning

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  1. B A Van der Reijden
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Correspondence to B A Van der Reijden.

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Van der Reijden, B., Massop, M., Simons, A. et al. The NDE1 gene is disrupted by the inv(16) in 90% of cases with CBFB–MYH11-positive acute myeloid leukemia. Leukemia 24, 857–859 (2010). https://doi.org/10.1038/leu.2009.290

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