Chronic myeloid leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cell, in which a reciprocal translocation between chromosomes 9 and 22 produces BCR-ABL1, the oncogenic tyrosine kinase that drives disease (1). In newly diagnosed CML patients, tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 are remarkably effective at eliminating most BCR-ABL1-positive cells, especially in the chronic phase (CP-CML). However, TKIs do not eliminate CML leukemic stem cells (LSCs), and while some studies have reported treatment-free remission following deep molecular response, life-long therapy is required to maintain remission in most patients. Understanding the mechanisms driving TKI resistance will inform treatment strategies aimed at curing the disease.
TKI resistance is often linked to point mutations in the BCR-ABL1 kinase domain that impair drug binding. However, many cases of clinical resistance occur in the absence of BCR-ABL1 mutations (2). BCR-ABL1-independent resistance is a feature of the CML LSC population, providing a reservoir of cells for disease recurrence via mechanisms that are not well understood. Our previous work demonstrated that CML stem and progenitor cells that are TKI-resistant, but lack explanatory BCR-ABL1 kinase domain mutations, are dependent on the activation of alternative signaling pathways, especially signal transducer and activator of transcription 3 (STAT3) (3). To better understand the transcriptional drivers of TKI resistance, we performed genome-wide expression analyses on TKI-resistant CML cells versus parental controls using RNA sequencing (RNA-seq). Analysis of this dataset implicated nuclear factor-kappa B (NF-kappaB) as the transcriptional driver of TKI resistance. NF-kappaB is known to regulate the expression of diverse gene targets in many different cancers, including chronic myeloid leukemia.
The ubiquitin-proteasome system (UPS) plays an important role in activating and terminating NF-kappaB signaling in many different scenarios. Interestingly, two members of the UPS, proteasome 26S subunit, non-ATPases 1 (PSMD1) and 3 (PSMD3), were upregulated in TKI-resistant CML cell lines and patient samples, and in blast phase (BP) versus chronic phase (CP) CML patients (Figure 1).
PSMD1 and PSMD3 were also identified as survival-critical genes in a previously published small hairpin RNA (shRNA) library screen for TKI resistance (4). PSMD1 and PSMD3 are members of the 19S regulatory complex in the 26S proteasome, regulating substrate recognition and binding (5, 6). In breast cancer, PSMD1 promoted cancer cell growth by inducing p53 protein degradation (5); PSMD3, in contrast, enhanced cancer cell growth by stabilizing human epidermal growth factor receptor 2 (HER2) from degradation (6). In acute myeloid leukemia (AML), patients with higher levels of PSMD3 mRNA were shown to have a worse overall survival than patients with lower levels of expression (7). In the present study, we report that PSMD1 and PSMD3 promote NF-kappaB protein expression and transcriptional activity in CML, and that STAT3 perpetuates this signal in scenarios of TKI resistance. Our data implicate PSMD1 and PSMD3 as novel potential targets for combination therapies in myeloid malignancies and possibly other cancers (Figure 2).
You can find additional details and results of this study at https://www.nature.com/articles/s41388-021-01732-6.
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