Sanjay S Patel1, Michael J Kluk1, Olga K Weinberg2. 1. Division of Hematopathology, Weill Cornell Medical College, New York, NY, USA. 2. Department of Pathology, Boston Children's Hospital, 300 Longwood Avenue, Bader 126.2, Boston, MA, 02115, USA. olga.weinberg@childrens.harvard.edu.
Abstract
PURPOSE OF REVIEW: Nucleophosmin (NPM1) mutations are encountered in myeloid neoplasia and are present in ~ 30% of de novo acute myeloid leukemia cases. This review summarizes features of mutant NPM1-related disease, with a particular emphasis on recent discoveries relevant to disease monitoring, prognostication, and therapeutic intervention. RECENT FINDINGS: Recent studies have shown that HOX/MEIS gene overexpression is central to the survival of NPM1-mutated cells. Two distinct classes of small molecule drugs, BH3 mimetics and menin-MLL interaction inhibitors, have demonstrated exquisite leukemic cell toxicity in preclinical AML models associated with HOX/MEIS overexpression, and the former of these has shown efficacy in older treatment-naïve NPM1-mutated AML patients. The results of ongoing clinical trials further investigating these compounds will be of particular importance and may alter the clinical management of patients with NPM1-mutated myeloid neoplasms. Significant scientific advancements over the last decade, including improved sequencing and disease monitoring techniques, have fostered a much deeper understanding of mutant NPM1 disease biology, prognostication, and opportunities for therapeutic intervention. These discoveries have led to the development of clinical assays that permit the detection and monitoring of mutant NPM1 and have paved the way for future investigation of targeted therapeutics using emerging cutting-edge techniques.
PURPOSE OF REVIEW: Nucleophosmin (NPM1) mutations are encountered in myeloid neoplasia and are present in ~ 30% of de novo acute myeloid leukemia cases. This review summarizes features of mutant NPM1-related disease, with a particular emphasis on recent discoveries relevant to disease monitoring, prognostication, and therapeutic intervention. RECENT FINDINGS: Recent studies have shown that HOX/MEIS gene overexpression is central to the survival of NPM1-mutated cells. Two distinct classes of small molecule drugs, BH3 mimetics and menin-MLL interaction inhibitors, have demonstrated exquisite leukemic cell toxicity in preclinical AML models associated with HOX/MEIS overexpression, and the former of these has shown efficacy in older treatment-naïve NPM1-mutated AMLpatients. The results of ongoing clinical trials further investigating these compounds will be of particular importance and may alter the clinical management of patients with NPM1-mutated myeloid neoplasms. Significant scientific advancements over the last decade, including improved sequencing and disease monitoring techniques, have fostered a much deeper understanding of mutant NPM1 disease biology, prognostication, and opportunities for therapeutic intervention. These discoveries have led to the development of clinical assays that permit the detection and monitoring of mutant NPM1 and have paved the way for future investigation of targeted therapeutics using emerging cutting-edge techniques.
Authors: Sanam Loghavi; Courtney D DiNardo; Ken Furudate; Koichi Takahashi; Tomoyuki Tanaka; Nicholas J Short; Tapan Kadia; Marina Konopleva; Rashmi Kanagal-Shamanna; Noushin R Farnoud; Sherry Pierce; Joseph D Khoury; Jeffrey L Jorgensen; Keyur P Patel; Naval Daver; Musa Yilmaz; L Jeffrey Medeiros; Hagop Kantarjian; Farhad Ravandi; Sa A Wang Journal: Br J Haematol Date: 2021-02-22 Impact factor: 6.998