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Home › Dataset Library › Defective K-Ras Oncoproteins Initiate Cancer In Vivo and Evolve to Overcome Impaired Effector Binding

Dataset: Defective K-Ras Oncoproteins Initiate Cancer In Vivo and Evolve to Overcome Impaired Effector Binding

The oncogenic proteins expressed in human cancer cells are exceedingly difficult targets for drug discovery due to intrinsic properties...

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The oncogenic proteins expressed in human cancer cells are exceedingly difficult targets for drug discovery due to intrinsic properties of the Ras GTPase switch. As a result, recent efforts have largely focused on inhibiting Ras-regulated kinase effector cascades, particularly the Raf/MEK/ERK and PI3 kinase/Akt/mTOR pathways. We constructed murine stem cell leukemia virus (MSCV) vectors encoding oncogenic K-RasD12 with additional “second site” amino acid substitutions that that impair PI3 kinase/Akt or Raf/MEK/ERK activation and performed bone marrow transduction/transplantation experiments in mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins induced aggressive clonal T lineage acute lymphoblastic leukemia (T-ALL). These leukemias exhibited a high frequency of somatic Notch1 mutations, which is also true of human T-ALL. Multiple independent T-ALLs restored full oncogenic Ras activity by acquiring “third site” mutations within the viral KrasD12 transgenes. Other leukemias with undetectable PTEN and elevated phosphoryated Akt levels showed a similar gene expression profile to human early T progenitor (ETP) T-ALL. Expressing oncoproteins that are defective for specific functions is a general strategy for assessing requirements for tumor maintenance and uncovering potential mechanisms of drug resistance in vivo. In addition, our observation that defective Kras oncogenes regain potent cancer initiating activity strongly supports simultaneously targeting distinct components of Ras signaling networks in the substantial fraction of cancers with RAS mutations. WT Balb/c mice were lethally irradiated and transplanted with WT Balb/c bone marrow cells transduced with MSCV-IRES-Kras mutant-GFP vectors. Mice developed T-cell lymphoproliferative disease.

Species:
mouse

Samples:
10

Source:
E-GEOD-28687

Updated:
Dec.12, 2014

Registered:
Nov.11, 2014


Factors: (via ArrayExpress)
Sample INPUT KRAS MUTATIONS CELL LINE
GSM710498 KrasG12D,E37G F1002
GSM710499 KrasG12D,E37G T1000
GSM710500 KrasG12D,E37G T2002
GSM71050 KrasG12D,E37G T4203
GSM710502 KrasG12D,Y64G F1006
GSM710503 KrasG12D,Y64G F1007
GSM710504 KrasG12D,Y64G T2006
GSM710505 KrasG12D,Y64G T3006
GSM710506 KrasG12D,Y64G T3104
GSM710507 KrasG12D,Y64G T4100

Tags

  • acute lymphoblastic leukemia
  • amino acid
  • bone
  • bone marrow
  • cancer
  • cell
  • disease
  • leukemia
  • lymphoblastic leukemia
  • lymphoproliferative disease
  • stem cell
  • stem cell leukemia

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