ArticleBlood2013
Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.
Article in Blood, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
- Article
- Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.JCI insight · 2023Article
- Article
- PI3K: A Crucial Piece in the RAS Signaling Puzzle.Cold Spring Harbor perspectives in medicine · 2018Review
- Mechanistic and Preclinical Insights from Mouse Models of Hematologic Cancer Characterized by Hyperactive Ras.Cold Spring Harbor perspectives in medicine · 2018Review
- Modeling of RAS complexes supports roles in cancer for less studied partners.BMC biophysics · 2017Article
- Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design.Nature reviews. Drug discovery · 2016Review
- Article
- Timing of the loss of Pten protein determines disease severity in a mouse model of myeloid malignancy.Blood · 2016Article
- K-Ras protein as a drug target.Journal of molecular medicine (Berlin, Germany) · 2016Review
- KRAS Engages AGO2 to Enhance Cellular Transformation.Cell reports · 2016Article
- KRAS insertion mutations are oncogenic and exhibit distinct functional properties.Nature communications · 2016Article
- Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation.Oncotarget · 2016Article
- Effects of p38α/β inhibition on acute lymphoblastic leukemia proliferation and survival in vivo.Leukemia · 2015Article
- Article
- Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation.Cancer cell · 2014Article
- Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting.Frontiers in oncology · 2014Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
Abstract
Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.