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Editor's note
Open Access | 
10.1172/JCI179105
Cytoplasmic transcription factor sequestration drives the pathogenesis of a rearranged leukemia
Ali Shilatifard
Find articles by Shilatifard, A. in: JCI | PubMed | Google Scholar
Published February 15, 2024 - More info
J Clin Invest. 2024;134(4):e179105. https://doi.org/10.1172/JCI179105.
© 2024 Editor This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
Several canonical translocations produce oncofusion genes that can initiate acute myeloid leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase (TurboID) in-frame with 3 favorable-risk AML oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11) and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their nuclear localization. However, CBFB::MYH11-TurboID–interacting proteins were largely cytoplasmic, probably because of an interaction of the MYH11 domain with several cytoplasmic myosin-related proteins. Using a variety of methods, we showed that the CBFB domain of CBFB::MYH11 sequesters RUNX1 in cytoplasmic aggregates; these findings were confirmed in primary human AML cells. Paradoxically, CBFB::MYH11 expression was associated with increased RUNX1/2 expression, suggesting the presence of a sensor for reduced functional RUNX1 protein, and a feedback loop that may attempt to compensate by increasing RUNX1/2 transcription. These findings may have broad implications for AML pathogenesis.
Authors
Ryan B. Day, Julia A. Hickman, Ziheng Xu, Casey D.S. Katerndahl, Francesca Ferraro, Sai Mukund Ramakrishnan, Petra Erdmann-Gilmore, Robert W. Sprung, Yiling Mi, R. Reid Townsend, Christopher A. Miller, Timothy J. Ley
The oncofusion genes created by chromosomal translocations frequently drive hematological malignancies. In general, the chimeric proteins resulting from these oncofusions initiate and drive cancer pathogenesis by disrupting specific cellular mechanisms regulating patterns of gene expression. For example, translocations involving chromosome 11q23, which are among the most common found in pediatric leukemias, create fusions of the MLL-encoding gene KMT2A with any of a large number of genes on other chromosomes. It was mechanistically demonstrated that several of these seemingly unrelated oncofusion partners encode subunits of an RNA polymerase II elongation factor now known as the super elongation complex (SEC) (1). Therefore, translocations involving chromosome 11q23 drive cancer by creating chimeric fusions of MLL to SEC subunits, disrupting SEC’s role in transcriptional elongation checkpoint control. In other cases, oncofusion protein chimeras may also affect transcription factor stability, alter patterns of chromatin binding, hijack enhancers, or otherwise disrupt transcriptional regulatory mechanisms.
In an elegant study from Tim Ley’s laboratory published recently in the JCI, Day et al. (2) defined another mechanism by which translocations can cause cancer, demonstrating that the CBFB::MYH1 oncofusion protein chimera drives oncogenesis by sequestering the transcription factor Runx1 in the cytoplasm.
The Runx family of transcription factors (Runx1, Runx2, and Runx3), which heterodimerize with mammalian core binding factor β (CBFB) to form the hematopoiesis regulator core binding factor (CBF), plays central roles in acute myeloid leukemias (AMLs) initiated by the RUNX1::RUNX1T1 and CBFB::MYH11 oncofusions (3). For RUNX1::RUNX1T1 AML, recruitment of repressor machinery to genomic loci bound by CBF downregulates CBF target genes, driving oncogenesis (3). For CBFB::MYH11 AML, however, the mechanisms driving pathogenesis were previously unclear. To address this, Day et al. (2) fused the TurboID promiscuous biotin ligase (4) to oncogenes in a proximity-based labeling strategy to identify protein factors interacting with protein complexes associated with the CBFB::MYH11 oncofusion protein.
This approach revealed numerous cytoplasmic proteins in the CBFB::MYH11-TurboID interactome, indicating that cytoplasmic CBFB::MYH11 retention that may occur due to interaction of MYH11 with myosin and related cytoplasmic proteins. Using molecular, biochemical, and cell biology methods, Day et al. (2) demonstrated that cytoplasmic CBFB::MYH11 retention in the cytoplasm resulted in sequestration of RUNX1 in the cytoplasm in a form of aggregates. RUNX1 aggregation due to CBFB::MYH11 retention in the cytosol was confirmed in primary human AML cells, suggesting that this is the actual mechanism of the disease in humans. Unexpectedly, Day et al. also found that CBFB::MYH11 increased expression of both RUNX1 and RUNX2 in the nucleus, suggesting the existence of an intriguing mechanism to sense and compensate for reduced CBF function.
Similar relocalization of transcription regulatory factors from the nucleus to the cytosol has previously been reported for solid tumors (5). It was recently reported that truncated mutant forms of MLL4, which is found in a large number of cancers and developmental disorders such as Kabuki syndrome, relocalize to the cytoplasm in animal models of cancer and samples from patients with bladder cancer (6). The elegant report of the cytoplasmic retention of the CBFB::MYH11 chimera and concomitant sequestration of the RUNX transcription factor in the JCI provides a mechanism by which oncofusion genes drive the pathogenesis of hematological malignancies, informing both prognosis and therapeutic development (2).
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