HNT-34

NRIP1 Knockdown Affects Proliferation, Viability, and Response to Retinoic Acid in Chromosome 3 Rearranged Acute Myeloid Leukemia Cells

Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. NRIP1 knockdown negatively affects the proliferation and survival of 3q-rearranged AML cells and increases their sensitivity to all-trans retinoic acid, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.

Fig. 1. Knockdown of NRIP1 induces apoptosis and increases sensitivity to all-trans retinoic acid in t(3;3) acute myeloid leukemia cells (Grasedieck, Sarah, et al. 2021).

Differential Nucleolar Stress Response in NPM1-Mutated Versus NPM1 wild-type AML cells

Acute myeloid leukemia (AML) with mutated NPM1 accounts for one-third of newly diagnosed AML. Despite recent advances, treatment of relapsed/refractory NPM1-mutated AML remains challenging, with the majority of patients eventually dying due to disease progression. Dactinomycin is a low-cost chemotherapeutic agent, which has been anecdotally reported to induce remission in NPM1-mutated patients, although its mechanism of action remains unclear. To explore whether NPM1-mutated cells may have lower thresholds for nucleolar stress response than NPM1 wild-type cells, we exposed to dactinomycin OCI-AML3 and IMS-M2 cells as well as OCI-AML2 and HNT-34 cells, all of which have detectable TP53 levels by western blot. We found that low-dose dactinomycin generates more efficient stress response in cells expressing NPM1 mutant compared to wild-type cells, suggesting that NPM1-mutated AML may be more sensitive to nucleolar stress.

Fig. 2. NPM1mut facilitates nucleolar stress response to dactinomycin (Gionfriddo, Ilaria, et al. 2021).