Normal bone marrow signal-transduction profiles: A requisite for enhanced detection of signaling dysregulations in AML

James Marvin, Suchitra Swaminathan, Geoffrey Kraker, Amy Chadburn, James Jacobberger, Charles Goolsby*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Molecular and cytogenetic alterations are involved in virtually every facet of acute myeloid leukemia (AML), including dysregulation of major signal-transduction pathways. The present study examines 5 phosphoproteins (pErk, pAkt, pS6, pStat3, and pStat5) in response to 5 cytokine/growth factors (stem cell factor [SCF], Flt-3/Flk-2 ligand [FL], granulocyte/macrophage-colony stimulating factor [GM-CSF], interleukin-3 [IL-3], and granulocyte-CSF [G-CSF]) within 7 immunophenotypically defined populations, spanning progenitor to mature myeloid/myelomonocytic cells in normal bone marrows with further comparison to AML samples. The normal cohort showed pathway-specific responses related to lineage, maturation, and stimulus. Heterogeneous-signaling responses were seen in homogeneous immunophenotypic subsets emphasizing the additive information of signaling. These profiles provided a critical baseline for detection of dysregulated signaling in AML falling into 4 broad categories, viz lack of response, increased activation, altered constitutive expression, and dysregulated response kinetics, easily identified in 10 of 12 AMLs. These studies clearly show robust and reproducible flow cytometry phosphoprotein analyses capable of detecting abnormal signal-transduction responses in AML potentially contributing to definitive reliable identification of abnormal cells. As functional correlates of underlying genetic abnormalities, signal-transduction abnormalities may provide more stable indicators of abnormal cells than immunophenotyping which frequently changes after therapy and disease recurrence.

Original languageEnglish (US)
Pages (from-to)e120-e130
JournalBlood
Volume117
Issue number15
DOIs
StatePublished - Apr 14 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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