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Cytoplasmic mutated nucleophosmin is stable in primary leukemic cells and in a xenotransplant model of NPMc⁺ acute myeloid leukemia in SCID mice

¹ Institute of Hematology, University of Perugia, Perugia, Italy
² Institute of Hematology, University of Foggia, Foggia, Italy
³ Hematopathology Section, Policlinico S. Orsola, University of Bologna, Bologna, Italy
⁴ Institute of Hematology, University "La Sapienza", Rome
⁵ Munich Leukemia Laboratory GmbH, Munich, Germany

Correspondence: Brunangelo Falini, MD, Institute of Hematology, University of Perugia, Perugia, Italy. E-mail: faliniem{at}unipg.it

We investigated the NPM1 mutation status or subcellular expression of NPM protein (nuclear vs. aberrant cytoplasmic) at diagnosis and relapse in 125 patients with acute myeloid leukemia from Italy and Germany. All 52 patients with acute myeloidleukemia carrying at diagnosis mutated or cytoplasmic NPM (NPMc⁺ acute myeloid leukemia) retained this feature at relapse. Notably, cytoplasmic mutated NPM has now been retained for eight years in a xenotransplant model of NPMc⁺ acute myeloid leukemia in immunodeficient mice. None of 73 acute myeloid leukemia patients carrying at diagnosis wild-type NPM1 gene or showing at immunohistochemistry nucleus-restricted expression of nucleophosmin (NPMc^– acute myeloid leukemia), which is predictive of NPM1 gene in germline configuration, acquired cytoplasmic mutated NPM at relapse. This finding further confirms that NPMc⁺ acute myeloid leukemia represents a primary event rather than a transformation stage of NPMc^– acute myeloid leukemia. The stability of cytoplasmic mutated NPM in patients with acute myeloid leukemia, even at relapse in extramedullary sites, and in a xenotransplant model, suggest this event is crucial for leukemogenesis and represents the rationale for monitoring minimal residual disease and molecular targeted therapy in NPMc⁺ acute myeloid leukemia.

Key words: acute myeloid leukemia, nucleophosmin, NPM, mutations, antibodies, immunohistochemistry.

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