Acute lymphoblastic leukemia (ALL) is a highly aggressive cancer. Numerous genetic subtypes of ALL have been identified, including Philadelphia chromosome-positive B-cell ALL (Ph+B ALL) which comprises approximately 25-30% of all adult ALL. Ph+B ALL is characterized by the t(9;22) chromosomal translocation that generates the BCR-ABL1 fusion gene resulting in abnormal tyrosine kinase signaling in B lymphoid progenitors that drives the development of leukemia. Ph+B ALL remains a tumor with poor prognosis despite improved results by targeting the BCR-ABL1 driver fusion protein with tyrosine kinase inhibitors (TKIs). More than 50-60% of patients relapse, including those receiving newer immunotherapeutic approaches. A better understanding of disease pathogenesis would aid the rational development of new targeted therapeutic approaches.
Approximately 5,200 people are diagnosed with a form of leukemia in Australia each year. It is estimated that approximately 1500 of these cases are acute forms. Blood cancers such as leukemia are notoriously difficult to treat in adults, with 50% of Australian patients experiencing a relapse after the first round of chemotherapy and subsequently becoming resistant to further treatment. Researchers have found a new way to potentially treat one of the most common forms of ALL. The study, conducted by the Peter MacCallum Cancer Center in Melbourne, Australia, was able to kill leukemia cells in the laboratory and stop the growth of tumor cells, after identifying two new proteins fundamental to the development of the aggressive disease. The findings could lead to improved treatment options in the future, with plans underway to develop a research-based clinical trial.Â
Associate Professor Ashley Ng, corresponding author of the paper, spent over a decade researching the ERG transcription factor that regulates genetic activity in the cell nucleus. Imbalances in this protein can lead to blood cancers, such as acute lymphoblastic leukemia. Her previous research had uncovered the protein’s critical role in blood disorders associated with Down syndrome and in the normal function of blood cells, including how B lymphocytes (which are essential for producing antibodies) develop. Examination of transcription factors from the Kyoto Encyclopedia of Genes and Genomes (KEGG; dysregulated genes in tumors section) identified upregulation of several transcription factors involved in B cell differentiation, including the ETS family transcription factor ERG, the well-known oncogene c-MYC and its partner MAX in both murine and human BCR-ABL1 B cells.
After analyzing the genes regulated by ERG and c-Myc, the scientists discovered that these proteins were actually master regulators of several important pathways and processes within the leukemia cell. The researchers then narrowed the list to focus on an essential pathway for protein production, known as ribosomal biogenesis. This led the team to focus on targeting a key gene essential for this pathway, RNA polymerase (POL I), which is also controlled by these master regulatory proteins. The gene helps direct an important process of cell growth and division that can lead to the development of cancer if it goes awry. By targeting POL I with inhibitors, researchers were able to kill leukemia cells and halt their growth in preclinical and human tissue models. The team used the first POL I inhibitor, called Pidnarulex (CX-5461).
Since inhibition of POL I transcription causes nucleolar breakdown and induction of the nucleolar stress response, the team evaluated the effect of CX-5461 on nucleolar integrity. In human and murine B-ALL cell lines, the drug reduced fibrillarin (FBL) staining that was localized to smaller punctate nucleolar domains as well as diffusely in the nucleoplasm, indicating significant nucleolar interference. FBL is a small nucleolar ribonucleoprotein that directs the methylation and processing of pre-rRNAs. Consistent with the well-established action of CX-5461 in activating the nucleolar stress response, treatment with CX-5461 was associated with upregulation of the tumor suppressor p53. This led the cells to programmed cell death or apoptosis. There have been poor results of targeting ETS factors (including c-Myc) with specific molecules.
Therefore, scientists hope to target the POL I enzyme in order to induce p53 and therefore tumor cells to commit suicide. Indeed, the parallel intervention of the aforementioned oncogenes has been directly demonstrated in clinical cases. A clinical research published in 2022 evaluated MYC and p53 expression, TP53 aberration, their relationship, and their impact on overall survival in acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Expression of p53 and MYC was present in 11.5% and 27.7% of ALL/LBL cases (n=20 and n=48), respectively. MYC expression was significantly correlated with p53 expression and TP53 aberration and p53 expression and MYC expression had an adverse impact on overall survival in patients with ALL/LBL. MYC and p53 dual expression as well as combined MYC expression and TP53 aberration had a negative impact on overall survival.
Considering that, beside the still-persisting failure in targeting c-Myc or ERG with dedicated molecules, also clinically-valid p53 direct enhancers have been difficult to develop or tp place, targeting p53 indirectly with Pidnarulex could be an easier way to treat resistant forms of leukemia.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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