Periodic Reporting for period 5 - iAML-lncTARGET (Targeting the transcriptional landscape in infant AML)
Reporting period: 2022-07-01 to 2023-06-30
Infants with blood cancer particularly suffer from the side effects of the necessary intensive chemotherapy and have a poor prognosis. This highlights the need for new and innovative treatment approaches. The iAML-lncTARGET research team and others have recently revealed the importance of areas in the genome for the development of blood cancer that were previously considered as “junk”. These areas are extremely large and produce a variety of long and short non-coding RNAs. The production of these RNAs is extremely cell type-specific. Therefore those RNAs can serve as unique therapeutic targets. Still, the identification of relevant and novel targetable RNAs is technically extremely difficult. We will investigate those areas and evaluate therapeutic options to overcome current obstacles in the treatment of infants with blood cancer.
The iAML-lncTARGET project, backed by the ERC, has revolutionized our comprehension of Acute Myeloid Leukemia (AML), especially in infants. By highlighting the paramount role of non-coding RNAs in AML, this research has upended previous paradigms and set new benchmarks in the field.
A pivotal breakthrough was the identification of miR-193b as an endogenous tumor suppressor. This discovery has not only broadened our therapeutic horizon but also led to the pioneering development of synthetic miR-193b mimics. These mimics stand out due to their efficacy and notably lower toxicity compared to conventional treatments.
Taking technological strides, the team harnessed the power of targeted CRISPR interference (CRISPRi) to spotlight MYNRL15 in hematopoietic stem/progenitor cell (HSPC) and AML signatures. This trailblazing initiative marked the inaugural comprehensive CRISPRi screen of lncRNAs within the AML spectrum. Through this, MYNRL15 was unveiled as a cornerstone in myeloid leukemia, offering a window into the intricate architectural dynamics of chromatin and the mechanisms governing the disease. Expanding on these insights, predictive metrics were formulated, pivoting around MYNRL15's characteristics. The unveiling of the C-LNC catalog (www.C-LNC.org) has been a game-changer, equipping researchers globally with a compass to navigate the labyrinth of lncRNA loci and unearth noncoding vulnerabilities across diverse cancer landscapes.
Another landmark revelation was the pivotal role of the non-coding RNA, HOXA10-AS, in specific AML variants. This discovery has positioned HOXA10-AS at the forefront as a promising therapeutic candidate, offering a fresh perspective on AML combat strategies.
Further enriching the research landscape is the meticulously crafted transcriptomic atlas of infant AML and fetal stem cells. This resource not only deepens our grasp on AML's intricacies but also led to the unearthing of a RUNX1 isoform imbalance in Down syndrome-associated myeloid leukemia, underscoring the profound influence of alternative splicing in cancer's genesis.
Lastly, in a quest for enhanced therapeutic modalities, the study unveiled potential synergistic pathways, spotlighting the combined might of inhibiting LSD1 and JAK-STAT signaling.
To encapsulate, the iAML-lncTARGET project's revelations are a confluence of meticulous planning and the serendipities innate to scientific endeavors. The journey has rendered both anticipated outcomes and novel insights, each augmenting our AML understanding and guiding us towards more potent treatment avenues.
The successful dissemination of the iAML-lncTARGET project's findings has been paramount to its overarching impact. Recognizing the significance of its discoveries, the team embarked on a multifaceted dissemination strategy. Academic journals, with their global readership, became the primary avenue for publishing breakthroughs, ensuring peer recognition and fostering further research collaborations. Beyond academia, findings were presented at international conferences, allowing for real-time feedback and interdisciplinary exchanges. Additionally, the creation of the dedicated website, www.C-LNC.org ensured that the broader scientific community could access the C-LNC catalog effortlessly. Furthermore, in a bid to reach non-specialist audiences and raise public awareness, the team engaged with media outlets and organized community outreach programs. This holistic approach to dissemination not only elevated the project's visibility but also fostered a collaborative spirit, driving forward the global fight against AML.
A pivotal breakthrough was the identification of miR-193b as an endogenous tumor suppressor. This discovery has not only broadened our therapeutic horizon but also led to the pioneering development of synthetic miR-193b mimics. These mimics stand out due to their efficacy and notably lower toxicity compared to conventional treatments.
Taking technological strides, the team harnessed the power of targeted CRISPR interference (CRISPRi) to spotlight MYNRL15 in hematopoietic stem/progenitor cell (HSPC) and AML signatures. This trailblazing initiative marked the inaugural comprehensive CRISPRi screen of lncRNAs within the AML spectrum. Through this, MYNRL15 was unveiled as a cornerstone in myeloid leukemia, offering a window into the intricate architectural dynamics of chromatin and the mechanisms governing the disease. Expanding on these insights, predictive metrics were formulated, pivoting around MYNRL15's characteristics. The unveiling of the C-LNC catalog (www.C-LNC.org) has been a game-changer, equipping researchers globally with a compass to navigate the labyrinth of lncRNA loci and unearth noncoding vulnerabilities across diverse cancer landscapes.
Another landmark revelation was the pivotal role of the non-coding RNA, HOXA10-AS, in specific AML variants. This discovery has positioned HOXA10-AS at the forefront as a promising therapeutic candidate, offering a fresh perspective on AML combat strategies.
Further enriching the research landscape is the meticulously crafted transcriptomic atlas of infant AML and fetal stem cells. This resource not only deepens our grasp on AML's intricacies but also led to the unearthing of a RUNX1 isoform imbalance in Down syndrome-associated myeloid leukemia, underscoring the profound influence of alternative splicing in cancer's genesis.
Lastly, in a quest for enhanced therapeutic modalities, the study unveiled potential synergistic pathways, spotlighting the combined might of inhibiting LSD1 and JAK-STAT signaling.
To encapsulate, the iAML-lncTARGET project's revelations are a confluence of meticulous planning and the serendipities innate to scientific endeavors. The journey has rendered both anticipated outcomes and novel insights, each augmenting our AML understanding and guiding us towards more potent treatment avenues.
The successful dissemination of the iAML-lncTARGET project's findings has been paramount to its overarching impact. Recognizing the significance of its discoveries, the team embarked on a multifaceted dissemination strategy. Academic journals, with their global readership, became the primary avenue for publishing breakthroughs, ensuring peer recognition and fostering further research collaborations. Beyond academia, findings were presented at international conferences, allowing for real-time feedback and interdisciplinary exchanges. Additionally, the creation of the dedicated website, www.C-LNC.org ensured that the broader scientific community could access the C-LNC catalog effortlessly. Furthermore, in a bid to reach non-specialist audiences and raise public awareness, the team engaged with media outlets and organized community outreach programs. This holistic approach to dissemination not only elevated the project's visibility but also fostered a collaborative spirit, driving forward the global fight against AML.
The involvement of several of the identified non-coding RNAs in the pathogenesis and progression in blood cancer has not been described before. Hence, testing their future therapeutic potential and specificity goes beyond the start of the art and is an ambitious aim until the end of the project.