Mutated nucleophosmin detects clonal multilineage involvement in acute myeloid leukemia: impact on WHO classification

Because of a lack of specific clonality markers, information on lineage involvement and cell of origin of acute myelold leukemia with normal karyotype (AML-NK), is missing. Because Nucleophosmin (NPM) gene is frequently mutated in AML-NK and causes aberrant NPM cytoplasmic localization (NPMc(+)), it was used as an AML lineage clonality marker. Clonal NPM exon 12 mutations were detected in myeloid, monocytic, erythrold, and megakaryocytic cells but not in fibroblasts or endothelia that were laser-microdissected from 3 patients with NPMc(+) AML. Aberrant cytoplasmic expression of mutated NPM proteins was identified with anti-NPM antibodies in 2 or more myeloid hemopoietic cell lineages in 99 (61.5%) of 161 of NPMc(+) AML paraffin-embedded bone marrow biopsies; lymphold involvement was excluded in 3 investigated cases. These findings suggest that NPMc(+) AML derives from either a common myeloid or earlier progenitor. Immunohistochemical studies show that varying combinations and ratios of NPMC+ leukemic cells from distinct lineages are responsible for heterogeneity within each French-American-British (FAB) classification type and for NPMc(+) AML failing into different FAB categories. These findings question the value of FAB criteria in subdividing the WHO category of "AML not otherwise characterized" and suggest that, for clinical use, NPMc(+) AML be provisionally regarded as a separate AML with prognostic significance. (Blood. 2006;108:4146-4155) (c) 2006 by The American Society of Hematology.