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

Abstract

How MYC promotes the development of cancer remains to be fully understood. Here, we report that the Zn(2+)-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.

ASCIZ/ATMIN is dispensable for ATM signaling in response to replication stress

“…S3 in [13] ). These contradictory findings for the replication stress response extend our findings that, in contrast to [7] and [25] , ASCIZ/ATMIN was also not required for non-canonical ATM activation by chloroquine-induced or hypotonic chromatin perturbations in MEFs (primary and immortalized) and B lymphocytes from our Asciz -null mice [13] , [22] , as well as in siRNA-treated human ASCIZ knock-down cell lines [13] . Furthermore, our results are also consistent with a recent report that ASCIZ/ATMIN was not required for the non-canonical ATM activation by another stimulus, hypoxia [15] .…”

“…However, it has recently become clear that ASCIZ has major DNA damage-independent functions as an essential Zinc-finger transcription factor. ASCIZ activates the expression of the multi-functional dynein light chain, DYNLL1 (also known as LC8) [19] , and thereby regulates crucial developmental processes, including the earliest stages of embryonic lung formation [13] , [20] , B cell development [21] and B cell lymphomagenesis [22] , and the production of myeloid cells [23] .…”

The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species

“…Dynll1 is a subunit of the dynein motor complex and is known for its role in vesicular transport (36). However, more recent work has shown that it may participate in other processes, (36,37,(49)(50)(51)(52). These additional roles may require Dynll1 to interact with additional partners in different organelles.…”

Marine Mollusk‐Derived Agents with Antiproliferative Activity as Promising Anticancer Agents to Overcome Chemotherapy Resistance

“…Vera et al . discovered that aplysqualenol is a ligand for the light chain of dynein type 1 (DYNLL1), which is suggestive of potential development of small‐molecule regulators of the dynein complex with applications in cancer treatment …”