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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

ABSTRACT

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

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