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

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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