The Transcription Factor ASCIZ and Its Target DYNLL1 Are Essential for the Development and Expansion of MYC-Driven B Cell Lymphoma

•Loss of ASCIZ or its target DYNLL1 delays lymphoma development in Eμ-Myc mice•DYNLL1 expression is hyper-activated in pre-leukemic Eμ-Myc B cell precursors•Loss of ASCIZ or DYNLL1 is synthetic lethal with oncogenic MYC in developing B cells•Deletion of Asciz in established Eμ-Myc tumors delays lymphoma progression

SummaryHow MYC promotes the development of cancer remains to be fully understood. Here, we report that the Zn2+-finger transcription factor ASCIZ (ATMIN, ZNF822) synergizes with MYC to activate the expression of dynein light chain (DYNLL1, LC8) in the murine Eμ-Myc model of lymphoma. Deletion of Asciz or Dynll1 prevented the abnormal expansion of pre-B cells in pre-cancerous Eμ-Myc mice and potentiated the pro-apoptotic activity of MYC in pre-leukemic immature B cells. Constitutive loss of Asciz or Dynll1 delayed lymphoma development in Eμ-Myc mice, and induced deletion of Asciz in established lymphomas extended the survival of tumor-bearing mice. We propose that ASCIZ-dependent upregulation of DYNLL1 levels is essential for the development and expansion of MYC-driven lymphomas by enabling the survival of pre-neoplastic and malignant cells.

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