Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Stevens, Brett M.; Khan, Nabilah; Am, D'Alessandro; Nemkov, Travis; Winters, Amanda; Jones, Courtney L.; Zhang, Wei; Pollyea, Daniel A.; Jordan, Craig T.

doi:10.1038/s41467-018-05984-x

Cited by 74 publications

(79 citation statements)

References 68 publications

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“…The change to translational activity is evocative of numerous studies showing that translational regulation is particularly important during hematopoiesis (Khajuria et al, 2018;Signer et al, 2014;Stevens et al, 2018;van Galen et al, 2018). The nature of this increased translation that we and others observe is still unclear.…”

Section: Discussionmentioning

confidence: 79%

“…Proteins involved in translation initiation --including eukaryotic initiation factors, ribosome subunits, positive and negative translational regulators, and ribosome biogenesis factors -are significantly affected. Despite a decrease in protein abundance for the GO category of translation initiation as a whole in wt/S34F cells compared to wt/w/t cells, protein synthesis is elevated in these cells, recapitulating the phenotype seen in human MDS stem cells (Stevens et al, 2018).…”

Section: Resultsmentioning

confidence: 88%

“…6C-D). Again, the elevated global mRNA translation levels in wt/S34F cells shows that the U2AF1 S34F mutation in progenitor cells in vitro is sufficient to recapitulate the elevated global translation observed in hematopoietic stem cells derived from MDS patients (Stevens et al, 2018).…”

Section: Wt/s34f Cells Depleted Of Npm1 Exhibit Cycle Progression Defmentioning

confidence: 87%

“…Similarly, recent evidence suggests that MDS is characterized by increased protein synthesis in the population of CD123+ MDS stem cells from human patients (Stevens et al, 2018). These malignant MDS stem cells show increased translation yet retain a quiescent phenotype and are predominantly in the G0 phase of the cell cycle.…”

Section: Introductionmentioning

confidence: 89%

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Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

Akef¹,

Cappell²,

Larson³

2019

Preprint

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U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3' splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis-regulation of the translation initiation and ribosome biogenesis machinery, with the potential for widespread translational changes. The net result is a global increase in mRNA translation at the single cell level.Among the translationally upregulated targets of U2AF1-S34F are Nucleophosmin1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of wt/S34F cells and causes rRNA processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1 and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation which recapitulates translational mis-regulation in myeloid disease.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 88%

Section: Wt/s34f Cells Depleted Of Npm1 Exhibit Cycle Progression Defmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 89%

See 2 more Smart Citations

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

Akef¹,

Cappell²,

Larson³

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…MDS is considered a stem cell‐derived disease (Stevens et al , ), which can affect either a single cell lineage or multiple lineages (Nilsson et al , ; Chung et al , ). However, research into MDS stem cells is less advanced than AML or CML, partly due to difficulties in establishing mouse models of the disease.…”

Section: Cancer Cell Metabolism In Myeloid Lscsmentioning

confidence: 99%

Energy metabolism and drug response in myeloid leukaemic stem cells

et al. 2019

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Summary Despite significant advances in the treatment of myeloid malignancies, many patients become resistant to therapy and ultimately succumb to their disease. Accumulating evidence over the past several years has suggested that the inadequacy of many leukaemia therapies results from their failure to target the leukaemic stem cell (LSC). For this reason, the LSC population currently represents the most critical target in the treatment of myeloid malignancies. However, while LSCs are ideal targets in the treatment of these diseases, they are also the most difficult population to target. This is due to both their heterogeneity within the LSC population, and also their phenotypic similarities with normal haematopoietic stem cells. This review will highlight the current landscape surrounding LSC biology in myeloid malignancies, with a focus on altered energy metabolism, and how that knowledge is being translated into clinical advances for the treatment of chronic and acute myeloid leukaemia and myelodysplastic syndromes.

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RNA binding protein‐directed control of leukemic stem cell evolution and function

Joshi,

Keyvani Chahi,

Liu

et al. 2024

HemaSphere

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Strict control over hematopoietic stem cell decision making is essential for healthy life‐long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease‐initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre‐leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age‐related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post–transcriptional control, where RNA‐binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post–transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post–transcriptional control as actionable targets for precision therapy of AML.

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Characterization and targeting of malignant stem cells in patients with advanced myelodysplastic syndromes

Cited by 74 publications

References 68 publications

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

Energy metabolism and drug response in myeloid leukaemic stem cells

RNA binding protein‐directed control of leukemic stem cell evolution and function

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