Abstract
Acute lymphoblastic leukemia (ALL) is a prevalent type of pediatric cancer, affecting approximately one-third of pediatric cancer patients (Goldberg et al., 2003). T-cell acute lymphoblastic leukemia (T-ALL) is known for its severity, with high rates of relapse, typically ranging from 30-40%, and resistance to chemotherapy (Raetz & Teachey 2016). B-cell acute lymphoblastic leukemia is recognized for its prevalence, accounting for 75-80% of ALL cases (“Key statistics for childhood leukemia,” 2023). It is important to recognize the underlying biological mechanisms that contribute to chemotherapy resistance. In attempt to answer the question, “What are the mechanisms underlying resistance to chemotherapy in Acute lymphoblastic leukemia (ALL), and how can these be overcome?” this review aims to focus on the biological mechanisms surrounding ALL.
Keywords: Acute lymphoblastic leukemia, T-cell Acute lymphoblastic leukemia, B-cell Acute lymphoblastic leukemia, drug resistance, genetic contributions to ALL treatment resistance, leukemic stem cells
Biological Mechanisms Underlying ALL Treatment Resistance 3 Exploring the Relapse of ALL using VASA-seq8
ALL is notorious for its high relapse rate, which poses significant dangers. These relapses can be categorized into two types: 1) originating from the major clone of the initial disease and 2) from a minor ancestral clone (Kunz et al., 2015; Oshima et al., 2016; Rishter et al., 2022). Type 1 relapses frequently activate the IL7 receptor pathway, while type 2 relapses are driven by activation of the transcription factor TAL1 and are enriched in mutations of cancer-predisposing genes [Rishter]. In a compelling study, researchers conducted single-cell full-length total RNA sequencing using VASA-seq8 to trace the evolution of treatment-resistant clones from initial diagnosis to relapse in the same patient (Costea et al., 2024). The study followed 18 patients and revealed a common, dormant stem-like cell phenotype in these individuals. This research sheds light on the underlying mechanisms of relapse in ALL and provides crucial insights into potential treatment strategies.
At the start of the disease, almost all the cancer cells (98.62%) belonged to one main group, called cluster 0 (Costea et al., 2024). By the time the patient relapsed, this group had shrunk to just 3.27% of the total cancer cells. Meanwhile, a small group of cells that only made up 1.37% at diagnosis (cluster 2) had expanded to 26.47% at relapse, showing that these cells likely survived treatment and grew back. A new group of cells (cluster 1) also emerged at relapse, making up 70.24% of the cancer cells. When looking closer, the researchers found that most of the cells in cluster 2 were in a resting phase of the cell cycle (called G1), and these cells were more immature than the other clusters, meaning they hadn't fully developed. This immaturity might help them resist chemotherapy. By comparing the genetic activity of these different clusters, it is suggested that cluster 2’s cells, which were dormant and less mature, are functionally different from other leukemia cells, possibly explaining why they are harder to eliminate with treatment. Using a technique called Gene Set Enrichment Analysis (GSEA), they found that certain pathways, like those involved in cell adhesion, NF-κB signaling, and TGF-β signaling, were highly active in these dormant cells, which are known to help cells resist drugs. These dormant cells had lower activity in energy-related processes – a common trait of stem-like cells (Costea et al., 2024).
Non-genetic Factors for ALL Treatment Resistance
Additionally, non-genetic factors such as clonal heterogeneity contribute to the survival of leukemic cells post-therapy. Clonal heterogeneity refers to genetic differences in a population of cells that are generally amplified by clonal expansion. This includes metabolic reprogramming that allows cells to evade cytotoxic effects (Calderon et al. 2023). For ALL that relapse, the most common type of treatment tends to be stem cell transplants (NIH). Mesenchymal stem cells, or MCSs, can induce the restoration of specific biosynthetic pathways in leukemia cells that are compromised by L-Asparaginase therapy. Some of these pathways include the asparagine synthesis pathway, which reactivates the synthesis of asparagine, amino acid metabolism, which allows for an alternative source of amino acids for leukemia cells, energy metabolism pathways, which helps leukemia cells retain energy, and nucleotide synthesis pathways, which are essential for ALL cell proliferation (Calderon et al., 2023). These biological processes are amplified by other hormonal imbalances or biochemical differences. For example, the cortisol hormone and its analogs can reduce immune system reactivity along with setting up the microenvironment where a tumor thrives, such as suppressing metabolic activities, accelerating tumor growth, and DNA damage.
The repression of biological pathways also plays a role in chemotherapy drug resistance in patients with ALL. For instance, PI3K/AKT signaling pathway by miR126 mediates the
stemness of leukemic stem cells and drug resistance (Niu et al., 2022). A protein called Integrin α6 helps leukemic cells survive chemotherapy by interacting with the bone marrow environment, particularly laminin (Alquezar-Artieda et al., 2020). This interaction promotes signaling pathways that protect leukemia cells from treatment. B-ALL cells adhere to various laminins using the protein integrin α6, which acts as a functional adhesion molecule (Alquezar-Artieda et al., 2020). This is important because bone marrow niches are rich in laminins. When Integrin α6 was blocked with an antibody (P5G10), the cells' attachment to bone marrow stromal cells (OP9) was significantly reduced, suggesting that these stromal cells may produce laminin-rich extracellular matrices (ECMs) to which the leukemia cells adhere. However, other α6-mediated interactions might also play a role (Alquezar-Artieda et al., 2020). Thus, the restoration and repression of certain biological pathways by MCSs, miR1126, and Integrin α6 is crucial for the cells’ survival and adaptation to treatment stress (Calderon et al., 2023). Leukemia stem cells, or LSCs, can also play a role in drug resistance by adapting to survive chemotherapy (Niu et al., 2022). Personalized treatment, intense monitoring, and the use of biomarkers are helpful for long-term treatment and resistance.
Genetic Factors for ALL Chemotherapy Resistance
Genetic differences play a significant role in the development of ALL, specifically B-cell acute lymphoblastic leukemia (B-ALL) in pediatric patients. Research has shown that genetic factors account for the majority of contributing elements to ALL, and that there are distinct DNA methylation and gene expression patterns related to drug resistance found in B-ALL patients, suggesting predetermined genetic profiles of ALL relapse (Enblad et al., 2023). The impact of genetics on ALL underscores the complexity of this disease and the importance of understanding the underlying genetic mechanisms. One key aspect of the treatment for B-ALL involves the use of glucocorticoids (GCs) such as prednisone and dexamethasone (Jędraszek et al., 2022). These GCs are essential in the management of acute lymphoblastic leukemia as they work by binding to the glucocorticoid receptor, known as NR3C1. Upon binding, they reduce inflammation and influence gene regulation, contributing to the treatment of B-ALL (Jędraszek et al., 2022). However, it's important to note that some patients develop resistance to steroids, which can be attributed to various factors. For instance, mutations in the NR3C1 gene or chromatin changes in resistant cells have been identified as causes of steroid resistance. This resistance to steroids complicates the treatment process and increases the risk of relapse for patients with B-ALL. Furthermore, the presence of mutations in genes such as CREBBP and NR3C2 complicates the landscape of B-ALL treatment, presenting additional challenges by altering transcriptional regulation, influencing blood pressure, electrolyte balance, and glucocorticoid sensitivity (Jędraszek et al., 2022). Researchers are exploring new therapeutic approaches by addressing steroid resistance and the complexities associated with genetic mutations in B-ALL.
Treatment
While considering novel treatment approaches, it is noted that this particular subset of cancer cells (B-ALL) have become resistant to innovative treatment approaches like CAR-T cell therapies and monoclonal antibodies (Jędraszek et al., 2022), likely due to their genetic differences. This presents a major challenge as this type of therapy is much newer, demonstrating how quickly cancer cells can adapt to new therapies and make treatment ineffective. One promising avenue involves the investigation of HDAC (histone deacetylase) inhibitors as potential strategies to overcome steroid resistance and enhance the efficacy of ALL treatment (Jędraszek et al., 2022). Others include gene therapy, personalized medicine, combination therapies that enhance NR3C2 and modulate glucocorticoid sensitivity, and targeted inhibition of CREBBP mutations. An alternate study found that leukemogenic-NRAS mutations might respond to MEK, autophagy, Akt, EGFR signaling, Polo−like kinase, Src signaling, and TGF-β receptor inhibition depending on the mutation profile (Zhang et al., 2022). These new therapeutic avenues are promising for the outcomes for patients with T-ALL and address the challenges posed by genetic factors and resistance mechanisms.
References
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