CRISPR Breakthrough: Targeting the Achilles’ Heel of AML – A Leap Towards Precision Oncology


Acute Myeloid Leukemia (AML) is a type of cancer that affects the blood and bone marrow. It’s characterized by an overproduction of immature white blood cells, known as myeloblasts or leukemic blasts. These abnormal cells crowd out normal blood cells, leading to a variety of symptoms and complications.  AML starts in the bone marrow, the soft inner part of certain bones where new blood cells are made. It can quickly move into the blood and sometimes spread to other parts of the body like the lymph nodes, liver, spleen, central nervous system, and testicles in males. There are several subtypes of AML, classified based on the type of cell from which the leukemia developed and its level of maturity. This classification is important for determining the prognosis and treatment plan. AML is diagnosed through blood tests, bone marrow aspiration and biopsy, cytogenetic analysis, and other laboratory tests to identify specific genetic mutations and changes. Treatment often involves chemotherapy, targeted therapy, and sometimes stem cell transplant. AML is characterized by the rapid proliferation of undifferentiated myeloid cells, often exacerbated by genetic mutations and cytogenetic aberrations. The current standard treatments for AML, including high-dose anthracycline and cytarabine, achieve high remission rates but are often associated with significant toxicity and a notable risk of relapse. As a result, there is an urgent need for novel, targeted therapies with lower inherent toxicity, particularly for elderly patients and for maintaining remission post-treatment. The specific treatment plan depends on various factors including the subtype of AML, the patient’s age, overall health, and genetic mutations present in the cancer cells. The outlook for AML patients varies based on several factors. Age, overall health, specific genetic mutations in the leukemia cells, and how well the cancer responds to treatment are crucial in determining the prognosis. Generally, younger patients with AML tend to have a better prognosis than older adults. Research continues to make advances in understanding AML, leading to the development of new treatments and therapies. For example, targeted therapies that focus on specific genetic changes in leukemia cells have become more common.

In a new study published in the Journal Leukemia by Signe Neldeborg, Johannes Frasez Soerensen, Charlotte Thornild Møller, Marie Bill, Zongliang Gao, Rasmus O. Bak, Kasper Holm, Boe Sorensen, Mette Nyegaard, Yonglun Luo, Peter Hokland, Magnus Stougaard, Maja Ludvigsen, and led by Professor Christian Kanstrup Holm from the Aarhus University in Demnark focused on AML, specifically targeting the t(8;21) fusion found in a substantial fraction of AML cases. The study showcases a groundbreaking dual intron-targeting CRISPR-Cas9 treatment strategy that can efficiently disrupt fusion genes without needing to pinpoint the precise breakpoint location. This method has demonstrated impressive efficacy in vitro, substantially reducing growth rate and proliferation in AML t(8;21) Kasumi-1 cells, and has also shown promising results in vivo.

The authors’ approach is based on the CRISPR-Cas9 gene editing system, which has shown promise in a range of genetic diseases. By targeting introns adjacent to the fusion breakpoint of the RUNX1-RUNX1T1 gene in AML t(8;21), the researchers circumvent the need for precise breakpoint identification. This strategy effectively disrupts the oncogenic driver while preserving the integrity of the wild-type RUNX1 and RUNX1T1 genes. The method is designed to be adaptable across patients, regardless of individual genetic variations in the breakpoint region. The researchers demonstrated this technique’s efficacy using the Kasumi-1 cell line model, where they observed significant reductions in cell proliferation and tumor growth in vitro. They also validated the approach in primary cells isolated from a patient with AML t(8;21), reinforcing the potential of this method in clinical settings. Additionally, the study highlights the importance of careful consideration regarding off-target effects and the feasibility of delivering CRISPR-Cas9 components in vivo. This study represents a critical step forward in the development of targeted gene therapies for AML and potentially other cancers characterized by specific genetic aberrations. The dual intron-targeting CR strategy provides a more precise and potentially safer approach to gene editing in cancer treatment. The ability to disrupt fusion genes without needing detailed knowledge of the breakpoint location is a significant advancement, allowing for broader applicability across patients with AML t(8;21). This approach could revolutionize the treatment paradigm for AML, offering a more targeted and less toxic alternative to traditional chemotherapy.

The implications of this study extend beyond AML. The principles and techniques developed here could be applied to other cancers driven by specific genetic aberrations. As our understanding of the genetic underpinnings of various cancers deepens, such targeted gene editing strategies could become a cornerstone of cancer therapy. However, the journey from bench to bedside is fraught with challenges. While the in vitro and in vivo data are promising, translating these findings into a clinically viable treatment will require extensive further research. Key considerations include optimizing the delivery mechanisms for CRISPR-Cas9 components in humans, ensuring the specificity and safety of the treatment, and determining the long-term outcomes and potential side effects. Additionally, the ethical implications of gene editing in humans must be carefully considered. In conclusion, the study led by Professor Holm and his team represents a breakthrough in the use of CRISPR-Cas9 for cancer treatment. By demonstrating the feasibility and efficacy of a dual intron-targeting strategy in AML t(8;21), they have opened the door to a new era of precision medicine in oncology. This approach has the potential to improve outcomes for patients with AML and possibly other cancers, offering hope for more effective and less toxic treatments. The journey ahead is complex and requires careful navigation, but the path forward is undoubtedly promising.

CRISPR Breakthrough: Targeting the Achilles' Heel of AML – A Leap Towards Precision Oncology - Medicine Innovates

About the author

Professor Christian Kanstrup Holm

Department of Biomedicine,
Aarhus University,

investigating the immune system during infection, and his research has been centered on finding out how the immune system detects and responds to infections, this has also included the defense against SARS-CoV2, which causes COVID-19.

A breakthrough has just hit this particular area of research. It has become clear that well-known biochemical mechanisms, those that regulate the energy turnover in cells, are central to the development of immunity. This is a central part of the research that takes place in Christian Kanstrup Holm’s laboratory. We want to understand how biochemical mechanisms such as glycolysis and the Kreb´s cycle affect the interaction between virus and host. The interest in the immune system became vague already during my thesis and PhD course, where I dealt with the herpes virus and the part of the immune system called the adaptive immune system. Later, the other part of the immune system, the innate immune system, caught my interest.


Signe Neldeborg, Johannes Frasez Soerensen, Charlotte Thornild Møller, Marie Bill, Zongliang Gao, Rasmus O. Bak, Kasper Holm, Boe Sorensen, Mette Nyegaard, Yonglun Luo, Peter Hokland, Magnus Stougaard, Maja Ludvigsen, Christian Kanstrup Holm. Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo. Leukemia, 2023; DOI: 10.1038/s41375-023-01950-9

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