title: Normal bone marrow signal-transduction profiles: a requisite for enhanced detection of signaling dysregulations in AML.
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.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
authors.forename: James
authors.initials: J
authors.lastname: Marvin
authors.forename: Suchitra
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Kraker
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: James
authors.initials: J
authors.lastname: Jacobberger
authors.forename: Charles
authors.initials: C
authors.lastname: Goolsby
mesh_terms: D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D007377:Interleukin-3 / Q000378:metabolism / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology
chemical_list: C508596:IL3 protein, human; D007377:Interleukin-3; D008565:Membrane Proteins; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; C084881:flt3 ligand protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases