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Molecular roulette: nucleophosmin mutations in AML are orchestrated through N-nucleotide addition by TdT by Julian Borrow; Sara A. Dyer; Susanna Akiki; Michael J. Griffiths is a Medicine article available to read on EtoBox.

What is Molecular roulette: nucleophosmin mutations in AML are orchestrated through N-nucleotide addition by TdT about?

Nucleophosmin (NPM1) is the most commonly mutated gene in acute myeloid leukemia (AML). AML with mutated NPM1 is recognized as a separate entity in the World Health Organization 2016 classification and carries a relatively favorable prognosis. NPM1 mutations are predominantly 4-bp duplications or insertions in the terminal exon that arise through an unknown mechanism. Here we analyze 2430 NPM1 mutations from 2329 adult and 101 pediatric patients to address their origin. We show that NPM1 mutations display the hallmarks of replication slippage, but lack suitable germline microhomology available for priming. Insertion mutations display G/C-rich N-nucleotide tracts, with a significant bias toward polypurine and polypyrimidine stacking (P < .001). These features suggest terminal deoxynucleotidyl transferase (TdT) primes replication slippage through N-nucleotide addition, with longer syntheses manifesting as N-regions. The recurrent type A, type D, and type B mutations require 1, 2, and 3 N-nucleotide extensions of T, CC, and CAT, respectively, with the last nucleotide used as occult microhomology. This TdT-mutator model successfully predicts the relative incidence of the 256 potential

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Author

Julian Borrow; Sara A. Dyer; Susanna Akiki; Michael J. Griffiths

Publisher

American Society of Hematology (ISSN 0006-4971)

Published

2019

Language

EN

Field

Medicine (Health Sciences)