Dissecting the mitochondrial alterations by aberrant NPM1 to the pathogenesis of myelodysplastic syndrome
Keisuke Ito
PhD, MDAlbert Einstein College of Medicine
Project Term: October 1, 2023 - September 30, 2026
Survival rates for those afflicted with MDS have not improved despite extensive effort to identify the key genetic events in its pathogenesis. This project elucidates the contributions of aberrant NPM1 to hematological disorders, with a focus on mitochondrial fitness and inflammasome activation. The resulting insights into the metabolic, genetic and proteomic requirements of homeostasis that are critical to preventing aging will have a major impact on the treatment of hematological malignancies.
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell (HSC) disorders that are characterized by ineffective production of blood cells and carry a high risk of transformation to myeloid leukemia. The pathophysiology of MDS involves multiple factors, not least of which is aging. The incidence of MDS increases with advancing age, and the median age at diagnosis is 65-70 years. However, it remains an open question whether age simply increases the probability of acquiring mutations or the cellular context itself contributes to pathogenesis, and dysregulation of innate immune signaling has recently been highlighted as a key factor in MDS pathogenesis. Nucleophosmin1 (NPM1) resides on 5q35 and is lost in ~10% of MDS arising from large 5q deletion. NPM1 is involved in multiple cellular processes but its roles in mitochondrial physiology have yet to be explored, even though mitochondrial abnormalities have been observed in MDS. Our established mouse model featuring conditional knockout (cKO) of Npm1 has revealed that its loss causes premature aging in HSCs. Npm1 loss also caused mitochondrial activation, which led to aberrant activation of the NLRP3 inflammasome, which correlated with uncontrolled expansion of the myeloid lineage. Interestingly, our team used a knock-in mouse model for the mutant form of Npm1 (Npm1c) to demonstrate that Npm1c also impairs mitochondrial function; however, the Npm1 cKO model gave rise to MDS followed by pancytopenia, a different pathological condition from that found in Npm1c models. This led us to hypothesize that NPM1 is a key regulator of mitochondrial fitness for HSC self-renewal and that mitochondrial alteration triggers inflammatory pathways which contribute to hematological disease. In this study, we will conduct comparative metabolic, transcriptomic and hematologic analyses of Npm1 cKO and mutant mice to establish the extra-nuclear roles of Npm1 in mitochondrial fitness, the ability of altered mitochondria to activate the Nlp3 inflammasome, and the consequences of this activation for hematological disease. We have three main goals: (1) to investigate the role of Npm1 in maintaining mitochondrial fitness, (2) to study the relationship between mitochondrial alteration and Nlrp3 inflammasome activation in hematopoietic homeostasis, and (3) to target therapeutically the Nlrp3 inflammasome and mitochondrial fitness in myeloid-biased hematopoiesis. The proposed research will lay the groundwork for extra-nuclear Npm1 as a key regulator of mitochondrial fitness and yield crucial insights into the mitochondrial alterations that trigger HSC aging through active inflammatory pathways, which in turn contribute to hematological malignancies.