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NPM1 is the most frequently mutated gene in acute myeloid leukemia (AML). Unfortunately, there are no ‘precision’ or rational treatments for this subtype of AML.To elucidate molecular mechanisms of pathogenesis, we performed the first comprehensive, unbiased analysis of the endogenous NPM1 protein-interactome using mass-spectrometry (LC-MS/MS). This approach identified abundant amounts of the master transcription factor driver of monocyte lineage-differentiation PU.1 (SPI1). The NPM1/PU.1 interaction causes PU.1 functional deficiency when NPM1 is mutated, because mutant-NPM1 dislocates PU.1 into the cytoplasm with it.This was confirmed using six different methods: (i) Immunoprecipitation (IP)-LC-MS/MS from nuclear and cytoplasmic fractions of wildtype (wt) and NPM1 -mutated AML cell lines (n=2); (ii) IP-Western blot (WB) from nuclear/cytoplasmic fractions of NPM1 -mutated/wt AML cell lines (n …