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|Title:||Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis|
|Citation:||Leukemia, 2018; 32(1):38-48|
|Publisher:||Nature Publishing Group|
|SJ Welsh, ML Churchman, M Togni, CG Mullighan and J Hagman|
|Abstract:||The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-β (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7)-independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function.|
|Keywords:||Lymphocytes; Cell Line, Tumor; Humans; Phosphotransferases; Receptor, Platelet-Derived Growth Factor beta; Trans-Activators; Membrane Proteins; Oncogene Proteins, Fusion; Transcription Factors; Interleukin-7; Signal Transduction; Cell Proliferation; Gene Expression Regulation; STAT5 Transcription Factor; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Carcinogenesis|
|Rights:||© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved|
|Appears in Collections:||Medicine publications|
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