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

• Published in: Cell reports (Cambridge) Vol. 14; no. 6; pp. 1488 - 1499
• Main Authors: Wong, David M., Li, Lingli, Jurado, Sabine, King, Ashleigh, Bamford, Rebecca, Wall, Meaghan, Walia, Mannu K., Kelly, Gemma L., Walkley, Carl R., Tarlinton, David M., Strasser, Andreas, Heierhorst, Jörg
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.02.2016; Elsevier
• Subjects: Animals; Apoptosis; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Cell Cycle - genetics; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Dyneins - deficiency; Dyneins - genetics; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - mortality; Lymphoma, B-Cell - pathology; Mice; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - pathology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - immunology; Signal Transduction; Survival Analysis; Transcription Factors - deficiency; Transcription Factors - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.01.012

How 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. [Display omitted] •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 Wong et al. show that loss of ASCIZ or its transcriptional target DYNLL1 dramatically delays the development of MYC-driven B cell lymphoma in mice. ASCIZ is essential for the MYC-dependent upregulation of DYNLL1 and survival of pre-malignant cells before they can give rise to lymphoma.