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Groundbreaking Study Reveals Insights into Chronic Myeloid Leukaemia Growth Rates
Recent research has shed new light on chronic myeloid leukaemia (CML), a form of cancer impacting the blood and bone marrow, particularly regarding its emergence and growth dynamics. The study represents a significant advancement in understanding the rapid proliferation of cancerous cells long before a formal diagnosis is made, revealing discrepancies in growth rates among different patients.
The Wellcome Sanger Institute researchers, in collaboration with other institutions, employed whole genome sequencing to examine the BCR::ABL1 fusion gene—an essential factor responsible for inducing CML. Their investigation focused on the initial appearance of this genetic alteration within blood cells and how swiftly cells harboring this change proliferate until the disease is diagnosed.
Published in the journal Nature, this research enriches the scientific community’s comprehension of the potency of the BCR::ABL1 gene in propelling cancer progression.
Chronic myeloid leukaemia arises due to a genetic rearrangement between chromosomes, specifically where part of the ABL1 gene from chromosome 9 fuses with the BCR gene from chromosome 22, forming the BCR::ABL1 fusion, historically known as the Philadelphia chromosome.
Despite the established association of the BCR::ABL1 gene with CML, there is limited knowledge about its development, the speed of cell proliferation post-fusion, and their implications for disease advancement.
In this study, the researchers examined over 1,000 whole genomes from individual blood cells of nine CML patients, aged between 22 to 81 years. This genomic investigation enabled them to construct phylogenetic trees, illustrating the ancestral connections between cells. This methodology allowed insights into the historical growth patterns of tumor cells and pinpointed the time of the gene fusion that initiates cancer development.
The phylogenetic analysis indicated that the BCR::ABL1 fusion gene typically emerges three to 14 years prior to a CML diagnosis. Following its emergence, the associated tumor clones expand dramatically, with annual growth rates occasionally exceeding 100,000 percent. This acceleration signifies the unique capability of the fusion gene to instigate cancerous cell growth—a stark contrast to the more gradual development observed in other blood cancers and solid tumors, which generally require numerous genetic alterations over time.
Further findings suggest that a patient’s age significantly influences tumor growth rates; younger patients exhibited much quicker proliferation of cells carrying the fusion gene compared to their older counterparts. Notably, patients with rapidly advancing CML also tend to have poorer responses to tyrosine kinase inhibitors (TKIs), which are the standard therapeutic approach for managing this condition. Given that approximately 20% of individuals do not respond to TKIs, this study underscores the importance of considering growth rates in therapeutic settings, although larger studies are necessary to confirm these initial observations.
The researchers also explored whether individuals might carry the BCR::ABL1 fusion gene without displaying any clinical symptoms, utilizing sequencing data and health records from over 200,000 participants in the American “All of Us” cohort. Their analysis suggested that nearly all individuals identified with the fusion gene were subsequently diagnosed with a blood disorder, indicating that the proliferation of BCR::ABL1 cells without related symptoms is improbable.
Overall, these findings accentuate the exceptional capacity of the BCR::ABL1 fusion gene to drive the proliferation of cancerous cells in CML. The variation in growth rates among patients holds potential for future clinical applications, potentially aiding in the prediction of treatment responses.
Dr. Aleksandra Kamizela, co-first author of the study and a resident doctor, emphasized the clinical significance: “Currently, healthcare providers utilize a reverse transcription polymerase chain reaction (RT-PCR) test to monitor patient responses to CML treatment. However, our study highlights the genetic distinctions that may not routinely be observable in clinical settings, advocating for a closer examination of cancer growth rates in future research.”
Dr. Jyoti Nangalia, senior author and a hematologist, summarized the study’s implications: “Our findings indicate that chronic myeloid leukaemia is distinct from other cancer types—solid tumors and even other blood cancers—due to its exceptionally rapid growth. Understanding this rapid timeline compared to the lengthy development in most cancers could help refine therapeutic strategies for patients who currently have subpar treatment responses.”
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