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Sequential drug tre...
Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia
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- Malyukova, Alena (author)
- Karolinska Institute
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- Lahnalampi, Mari (author)
- University of Eastern Finland
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- Falqués-Costa, Ton (author)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,MLL-rearrangerad leukemi hos spädbarn,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Pölönen, Petri (author)
- University of Eastern Finland
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- Sipola, Mikko (author)
- University of Eastern Finland
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- Mehtonen, Juha (author)
- University of Eastern Finland
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- Teppo, Susanna (author)
- Tampere University Hospital
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- Akopyan, Karen (author)
- Karolinska Institute
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- Viiliainen, Johanna (author)
- Karolinska Institute
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- Lohi, Olli (author)
- Tampere University Hospital
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- Hagström-Andersson, Anna K. (author)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,MLL-rearrangerad leukemi hos spädbarn,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Heinäniemi, Merja (author)
- University of Eastern Finland
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- Sangfelt, Olle (author)
- Karolinska Institute
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(creator_code:org_t)
- 2024
- 2024
- English.
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In: Genome Biology. - 1474-7596 .- 1474-760X. ; 25:1
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https://lup.lub.lu.s...
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Abstract
Subject headings
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- Background: Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side-effects of chemotherapy. However, efficacy of precision therapies is limited in part because of tumor cell heterogeneity. A better mechanistic understanding of how drug effect is linked to cancer cell state diversity is crucial for identifying effective combination therapies that can prevent disease recurrence. Results: Here, we characterize the effect of G2/M checkpoint inhibition in acute lymphoblastic leukemia (ALL) and demonstrate that WEE1 targeted therapy impinges on cell fate decision regulatory circuits. We find the highest inhibition of recovery of proliferation in ALL cells with KMT2A-rearrangements. Single-cell RNA-seq and ATAC-seq of RS4;11 cells harboring KMT2A::AFF1, treated with the WEE1 inhibitor AZD1775, reveal diversification of cell states, with a fraction of cells exhibiting strong activation of p53-driven processes linked to apoptosis and senescence, and disruption of a core KMT2A-RUNX1-MYC regulatory network. In this cell state diversification induced by WEE1 inhibition, a subpopulation transitions to a drug tolerant cell state characterized by activation of transcription factors regulating pre-B cell fate, lipid metabolism, and pre-BCR signaling in a reversible manner. Sequential treatment with BCR-signaling inhibitors dasatinib, ibrutinib, or perturbing metabolism by fatostatin or AZD2014 effectively counteracts drug tolerance by inducing cell death and repressing stemness markers. Conclusions: Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell cycle and cell fate regulation, and a rationale for sequential administration of WEE1 inhibitors with low toxicity inhibitors of pre-BCR signaling or metabolism.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- AZD1775
- B-ALL
- BCL6
- Cell state transition
- Chromatin state
- KMT2A-r
- Leukemia
- Pre-BCR
- RUNX1
- Single-cell multiomics
- WEE1
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Malyukova, Alena
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Lahnalampi, Mari
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Falqués-Costa, T ...
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Pölönen, Petri
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Sipola, Mikko
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Mehtonen, Juha
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Teppo, Susanna
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Akopyan, Karen
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Viiliainen, Joha ...
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Lohi, Olli
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Hagström-Anderss ...
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Heinäniemi, Merj ...
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Sangfelt, Olle
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Genome Biology
- By the university
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Lund University
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Karolinska Institutet