Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia

Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a...

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Bibliographic Details
Published in:	Leukemia Vol. 31; no. 9; pp. 1962 - 1974
Main Authors:	Fisher, D A C, Malkova, O, Engle, E K, Miner, C A, Fulbright, M C, Behbehani, G K, Collins, T B, Bandyopadhyay, S, Zhou, A, Nolan, G P, Oh, S T
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-09-2017 Nature Publishing Group
Subjects:	1-Phosphatidylinositol 3-kinase 13/31 45/100 631/1647/1407 631/67/1990/2331 631/80/86 692/4028/67/1990/283/1897 692/699/1541/1990/2331 96/95 Acute myelocytic leukemia Acute myeloid leukemia Analysis Antigens, CD34 Bone Marrow Cancer Research Care and treatment CD34 antigen Cell Line Critical Care Medicine Cytometry Effectors Flow Cytometry - methods Gene expression Gene mutation Gene set enrichment analysis Hematology Hematopoiesis Humans Intensive Internal Medicine Janus kinase 2 Janus Kinase 2 - genetics Kinases Leukemia Leukemia, Myeloid, Acute - etiology Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology MAP kinase Mass spectrometry Medicine Medicine & Public Health Mutation Myelofibrosis Myeloid leukemia Myeloproliferative diseases Myeloproliferative disorders Neoplasms NF-kappa B - metabolism NF-κB protein Oncology original-article Phenotypes Primary Myelofibrosis - metabolism Primary Myelofibrosis - pathology Signal Transduction Signaling
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Summary:	Myeloproliferative neoplasms (MPNs) feature a malignant clone containing the JAK2 V617F mutation, or another mutation causing dysregulated JAK2 kinase activity. The multiple disease phenotypes of MPNs, and their tendency to transform phenotypically, suggest pathophysiologic heterogeneities beyond a common phenomenon of JAK2 hyperactivation. JAK2 has the potential to activate multiple other signaling molecules, either directly through downstream effectors, or indirectly through induction of target gene expression. We have interrogated myeloproliferative signaling in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) patient samples using mass cytometry, which allows the quantitative measurement of multiple signaling molecules simultaneously at the single-cell level, in cell populations representing a nearly complete spectrum of hematopoiesis. MF and sAML malignant cells demonstrated a high prevalence of hyperactivation of the JAK-STAT, MAP kinase, PI3 kinase and NFκB signaling pathways. Constitutive NFκB signaling was evident across MF and sAML patients. A supporting gene set enrichment analysis (GSEA) of MF showed many NFκB target genes to be expressed above normal levels in MF patient CD34+ cells. NFκB inhibition suppressed colony formation from MF CD34+ cells. This study indicates that NFκB signaling contributes to human myeloproliferative disease and is abnormally activated in MF and sAML.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2016.377