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Related Concept Videos

The Ras Gene02:38

The Ras Gene

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
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The role of the RAS pathway in iAMP21-ALL.

S L Ryan1, E Matheson1, V Grossmann2

  • 1Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.

Leukemia
|May 12, 2016
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Summary

Intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) is linked to frequent RAS pathway mutations. Targeting this pathway with MEK inhibitors shows promise for treating this high-risk ALL subtype.

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Area of Science:

  • Genomics
  • Oncology
  • Molecular Biology

Background:

  • Intrachromosomal amplification of chromosome 21 (iAMP21) defines a high-risk group of acute lymphoblastic leukemia (ALL).
  • Understanding the genomic alterations in iAMP21-ALL is crucial for identifying potential targeted therapies and improving patient outcomes.
  • The mutation rate and landscape of iAMP21-ALL require further investigation to guide treatment strategies.

Purpose of the Study:

  • To investigate the genomic landscape of iAMP21-ALL, focusing on mutations within the RAS/MEK/ERK pathway.
  • To determine the frequency and heterogeneity of RAS pathway mutations in a cohort of iAMP21-ALL patients.
  • To assess the potential of MEK inhibitors as a targeted therapy for iAMP21-ALL.

Main Methods:

  • Whole-exome sequencing was performed on eight iAMP21-ALL samples.
  • Targeted sequencing was conducted on a larger cohort of 42 diagnostic iAMP21-ALL samples.
  • In vitro studies using primary xenografts assessed the response to the MEK1/2 inhibitor, selumetinib.

Main Results:

  • A high mutation rate was observed in iAMP21-ALL samples, with frequent mutations identified in the RAS/MEK/ERK pathway.
  • RAS pathway mutations were present in 60% (25/42) of diagnostic iAMP21-ALL samples, with significant heterogeneity observed.
  • Constitutive RAS pathway activation was detected in samples with clonal mutations (≥35% VAF).
  • iAMP21 cells showed reduced viability upon treatment with the MEK1/2 inhibitor selumetinib in vitro.

Conclusions:

  • RAS pathway mutations are a common feature of iAMP21-ALL, suggesting its role in disease pathogenesis.
  • The presence of clonal RAS pathway mutations in a subset of patients indicates potential susceptibility to targeted MEK inhibition.
  • Targeted therapy directed at the RAS pathway may offer a novel therapeutic strategy to improve outcomes for high-risk iAMP21-ALL patients.