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Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia

Malyukova, Alena ; Lahnalampi, Mari ; Falqués-Costa, Ton LU ; Pölönen, Petri ; Sipola, Mikko ; Mehtonen, Juha ; Teppo, Susanna ; Akopyan, Karen ; Viiliainen, Johanna and Lohi, Olli , et al. (2024) In Genome Biology 25(1).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AZD1775, B-ALL, BCL6, Cell state transition, Chromatin state, KMT2A-r, Leukemia, Pre-BCR, RUNX1, Single-cell multiomics, WEE1
in
Genome Biology
volume
25
issue
1
article number
143
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85194997573
  • pmid:38822412
ISSN
1474-7596
DOI
10.1186/s13059-024-03260-4
language
English
LU publication?
yes
id
666e99c1-4522-456b-ac1c-4a02b5e24da3
date added to LUP
2024-07-03 10:43:18
date last changed
2024-07-03 10:47:20
@article{666e99c1-4522-456b-ac1c-4a02b5e24da3,
  abstract     = {{<p>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.</p>}},
  author       = {{Malyukova, Alena and Lahnalampi, Mari and Falqués-Costa, Ton and Pölönen, Petri and Sipola, Mikko and Mehtonen, Juha and Teppo, Susanna and Akopyan, Karen and Viiliainen, Johanna and Lohi, Olli and Hagström-Andersson, Anna K. and Heinäniemi, Merja and Sangfelt, Olle}},
  issn         = {{1474-7596}},
  keywords     = {{AZD1775; B-ALL; BCL6; Cell state transition; Chromatin state; KMT2A-r; Leukemia; Pre-BCR; RUNX1; Single-cell multiomics; WEE1}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Genome Biology}},
  title        = {{Sequential drug treatment targeting cell cycle and cell fate regulatory programs blocks non-genetic cancer evolution in acute lymphoblastic leukemia}},
  url          = {{http://dx.doi.org/10.1186/s13059-024-03260-4}},
  doi          = {{10.1186/s13059-024-03260-4}},
  volume       = {{25}},
  year         = {{2024}},
}