Acute Myeloid and Lymphoblastic Leukemias: A NPM1 Targeting Strategy

Leukemia, a wide spectrum of diseases with altered proliferation and differentiation capacity of myeloid and lymphoid blood progenitors, is the most frequent type of cancer in children and one of the most common in adults. We discovered a covalent small-molecule “probe” for the treatment of acute myeloid and lymphoblastic leukemias that allows for post-translational modulation of the proteome in these leukemia cells. The probe dramatically induces apoptosis of leukemic cells at sub-toxic doses and consistently reduces proliferation, impairs cellular metabolism and promotes chemosensitization to “standard-of-care” chemotherapy regimens. Our proteomic analysis found specific targets that are critical to the leukemia cell survival, namely Nucleophosmin (NPM1) protein, which is a nucleolar phosphoprotein that performs diverse biological functions including molecular chaperoning, ribosome biogenesis, DNA repair, and genome stability. NPM1 gene mutations represent the most common genetic lesion in adult acute myeloid leukemia and their prognostic relevance earned them recognition as a distinct entity in the 2017 World Health Organization (WHO) classification of hematopoietic neoplasms. Our findings suggest a critical role of covalent inhibition of NPM1 in maintaining acute myeloid and lymphoblastic leukemia cells survival. This finding provides a rationale for therapeutic NPM1 modulation in acute leukemias.