Abstract
Despite centuries of research progress, cancer remains challenging to understand and treat, persisting as a prominent contributor to global mortality. Childhood cancer is rare, however it remains a leading cause of death from illness in children. Pediatric cancer requires special attention due to differences from adult cancer, with fewer genetic
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mutations and less association with lifestyle factors. A distinct approach is needed, considering the long-term effects on children.
Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, accounting for 20% of cases. Although overall pediatric ALL treatment has improved, infants (under 1 year) with ALL, constituting 5% of cases, still face a lower survival rate. Infant ALL is marked by an 80% occurrence of chromosomal abnormalities in the KMT2A gene, leading to a highly aggressive form with a unique biology. Current treatment protocols yield a 40% survival rate for infants with KMT2A-rearranged ALL.
As demonstrated previously, KMT2A-rearranged infant ALL is characterized by aberrant DNA methylation patterns, which led to the evaluation of DNA methyltransferase inhibitors. While in vitro cytotoxicity has been observed, data on the in vivo efficacy of demethylating agents were lacking. Therefore, the in vivo anti-leukemic potential of low and clinically relevant decitabine doses in a human KMT2A-rearranged ALL xenograft mouse model was assessed. Additionally, a prolonged low-dose decitabine exposure was evaluated for sensitization of ALL cells to conventional chemotherapy and other epigenetic-based and anti-neoplastic compounds.
Acquired resistance to DOT1L inhibition, a class of epigenetic drugs targeting KMT2A-rearranged acute leukemias, was investigated. KMT2A-rearranged leukemias arise from a fusion between the KMT2A gene and another gene, forming abnormal KMT2A fusion proteins that attract DOT1L, leading to abnormal gene regulation and leukemia development. An extensively characterized cell line model of acquired resistance to the primary DOT1L inhibitor, pinometostat, offered insights into the adaptive capacity of KMT2A-rearranged ALL cells. These cells evade the effects of DOT1L inhibitors by adopting myeloid-associated characteristics and/or exhibiting cellular plasticity.
The observation that KMT2A-rearranged ALL cells can overcome their dependency on DOT1L, a crucial oncogenic property of this type of leukemia, raises the question whether there are other specific epigenetic vulnerabilities in these cells. Additional epigenetic regulators and essential kinases for KMT2A-rearranged ALL cells were identified utilizing CRISPR-Cas9 technology, revealing new molecular dependencies and potential therapeutic targets, including ARID4B, MBD3, and BMPR2. Ongoing investigations focus on understanding the roles of these targets in the context of KMT2A-rearranged ALL and exploring their treatment potential
Understanding how KMT2A-rearranged ALL cells drive leukemogenesis and identifying therapeutic strategies is crucial. Equally imperative is comprehending mechanisms underlying leukemia relapse within current treatment regimens. Therefore, single-cell RNA sequencing was utilized to analyze gene expression in individual leukemia cells from diagnostic samples of infants with KMT2A-rearranged ALL providing. By categorizing cells as 'resistant' or 'sensitive' to treatment, we identified subpopulations predicting future relapses in individual patients. This insight into therapy-resistant cells at diagnosis is pivotal for understanding recurrence mechanisms and developing preventive measures, shedding light on the complex biology of leukemia relapse.
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