MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis

Journal article

Katsarou, A., Trasanidis, N., Ponnusamy, K., Kostopoulos, I., Alvarez-Benayas, J., Papaleonidopoulou, F., Keren, K., Sabbattini, P.M. R., Feldhahn, N., Papaioannou, M., Hatjiharissi, E., Sudbery, I., Chaidos, A., Caputo, V. and Karadimitris, A. (2023). MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis. Blood Advances. 7 (21), pp. 6395-6410. https://doi.org/10.1182/bloodadvances.2023009772
AuthorsKatsarou, A., Trasanidis, N., Ponnusamy, K., Kostopoulos, I., Alvarez-Benayas, J., Papaleonidopoulou, F., Keren, K., Sabbattini, P.M. R., Feldhahn, N., Papaioannou, M., Hatjiharissi, E., Sudbery, I., Chaidos, A., Caputo, V. and Karadimitris, A.
AbstractDeregulated expression of lineage-affiliated transcription factors (TFs) is a major mechanism of oncogenesis. However, how the deregulation of nonlineage affiliated TF affects chromatin to initiate oncogenic transcriptional programs is not well-known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by the activation of enhancers and superenhancers, previously inactive in healthy B cells and plasma cells, and the cooperation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with the features of superenhancers, leading to the activation of the MAF-specific oncogenic transcriptome and the acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent, thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance.
KeywordsHematology
Year2023
JournalBlood Advances
Journal citation7 (21), pp. 6395-6410
PublisherAmerican Society of Hematology
ISSN2473-9529
2473-9537
Digital Object Identifier (DOI)https://doi.org/10.1182/bloodadvances.2023009772
Web address (URL)https://ashpublications.org/bloodadvances/article/doi/10.1182/bloodadvances.2023009772/496007/MAF-functions-as-a-pioneer-transcription-factor
Publication dates
Print25 Oct 2023
Publication process dates
Accepted05 May 2023
Deposited21 Nov 2023
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