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Nf1 gene inactivation in acute myeloid leukemia cells confers cytarabine resistance through MAPK and mTOR pathways

Leukemia volume 20, pages 151–154 (2006)Cite this article

Cytarabine (1-b-D-arabinofuranosyl-cytosine, Ara-C) is the major chemotherapeutic component in the treatment of acute myeloid leukemia (AML), and causes leukemia cell death following incorporation into replicative DNA. Patients with AML respond to Ara-C-based therapy quite variably. AML with certain cytogenetic features, such as t(15;17), t(8;21) and inv(16), confer a good prognosis, whereas others, such as those with abnormalities of chromosome 5 or 7, trisomy 8 and 11q23, are associated with worse prognostic subgroups. This provides a clue that different genetic abnormalities may be associated with variable responses to antileukemic drugs such as Ara-C. Although biochemical studies have implicated some alterations in Ara-C resistance,1 genetic mechanisms of chemoresistance are largely unknown.

NF1 tumor suppressor gene loss-of-function causes NF1 syndrome-associated myeloid malignancies, particularly juvenile myelomonocytic leukemia (JMML), which can undergo transformation to an acute leukemia. The NF1 gene protein product, neurofibromin, is a GTPase-activating protein (GAP) with activity for N-, K-, H- and R-RAS proteins and as such is a negative regulator of Ras signaling. Loss of NF1 in JMML cells may be functionally equivalent to an activating RAS gene point mutation, since these genetic events are mutually exclusive in this disease. Mouse modeling studies demonstrate that Nf1 gene loss in hematopoietic cells can cause myeloid malignancy.3, 4 Unfortunately, NF1-associated leukemias, such as JMML, tend to have a poor prognosis.4 The response of Nf1-deficient AML to Ara-C treatment has not been examined yet.

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Acknowledgements

This work is supported by the Leukemia and Lymphoma Society of America (LLS 7019–04, Specialized Center of Research).

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  1. Department of Genetics, Cell Biology and Development, The Cancer Center at the University of Minnesota, University of Minnesota, Minneapolis, MN, USA

    B Yin, K Morgan, D E Hasz, Z Mao & D A Largaespada

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  1. B Yin
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Yin, B., Morgan, K., Hasz, D. et al. Nf1 gene inactivation in acute myeloid leukemia cells confers cytarabine resistance through MAPK and mTOR pathways. Leukemia 20, 151–154 (2006). https://doi.org/10.1038/sj.leu.2404033

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