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 70 publications

(75 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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Integrative single‐cell expression and functional studies unravels a sensitization to cytarabine‐based chemotherapy through HIF pathway inhibition in AML leukemia stem cells

Velasco‐Hernandez,

Trincado,

Vinyoles

et al. 2024

HemaSphere

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Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy‐resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML‐LSCs and may represent a therapeutic target to sensitize AML‐LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single‐cell expression atlas of 119,000 AML cells and AML‐LSCs in paired diagnostic‐relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML‐LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard‐of‐care chemotherapy to impair AML growth and to substantially eliminate AML‐LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell‐driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy‐based approaches to specifically eliminate AML‐LSCs.

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

Cited by 70 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

Integrative single‐cell expression and functional studies unravels a sensitization to cytarabine‐based chemotherapy through HIF pathway inhibition in AML leukemia stem cells

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