Combination Therapy Shows Promise in *NUP98*-Rearranged Pediatric AML
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- Combination Therapy Shows Promise in *NUP98*-Rearranged Pediatric AML
A novel therapeutic approach combining menin inhibition with KAT6A/7 inhibition has demonstrated significantly improved survival rates in preclinical models of *NUP98*-rearranged pediatric acute myeloid leukemia (AML), according to a recent study published in *Cancer Discovery*. The findings suggest a potential breakthrough for treating this arduous-to-treat leukemia, even in cases resistant to existing therapies.
Targeting *NUP98*-Rearranged AML: A New Strategy
Researchers have identified the MYST gene family histone acetyltransferases complex proteins, specifically KAT6A/MOZ, KAT7/HBO1, and the KAT6A/7 complex subunit BRPF1, as therapeutically actionable dependencies for *NUP98*-rearranged pediatric AML. This discovery opens new avenues for targeted therapies aimed at disrupting the mechanisms driving this aggressive form of leukemia.
Did You Know? *NUP98* fusion oncoproteins drive leukemogenesis in approximately 5% of pediatric AML cases, with a higher prevalence in specific subtypes like monocytic, megakaryoblastic, and erythroid AML.
The Synergistic Effect of Menin and KAT6A/7 Inhibition
The study revealed that inhibiting both menin and KAT6A/7 resulted in a synergistic effect,significantly improving survival in AML model systems. This combination therapy proved effective even in cells that had developed resistance to menin inhibitors alone, highlighting it’s potential to overcome treatment resistance. According to the National Cancer Institute, targeted therapies are becoming increasingly critically important in cancer treatment, offering more precise and effective approaches [1].
“We have made a major advance in our understanding of these difficult-to-treat leukemias,” stated Dr. Charles G. Mullighan, MBBS(Hons), MSc, MD, of st. Jude Children’s Research Hospital, a senior co-corresponding author of the study. “We used that knowledge to provide a strong clinical rationale to try this combined approach that had striking results.”
Pro Tip: Identifying and targeting molecular dependencies in cancer cells is a key strategy in developing effective targeted therapies.
Study Details and Key Findings
The researchers employed genome editing techniques to identify genes interacting with *NUP98* fusion proteins, pinpointing MOZ/KAT6A and HBO1/KAT7 as critical dependencies. They found that MYST histone acetyltransferases are molecular dependencies in *NUP98*-rearranged AML, associating with *NUP98* fusion oncoproteins on chromatin. Genetic inactivation or pharmacological inhibition of KAT6A/7 impaired the cell fitness of *NUP98* rearrangements.
KAT6A/7 inhibition led to decreased global H3K23ac levels, displaced *NUP98* from chromatin, promoted myeloid cell differentiation, and decreased leukemic burden. The combination of KAT6A/7 inhibition with menin inhibition demonstrated synergistic effects in *NUP98*-rearranged leukemia xenograft mouse models and proved effective in menin inhibitor-resistant cells.
| Treatment | Outcome |
|---|---|
| Menin Inhibition | Extended survival in mouse models |
| KAT6A/7 Inhibition | Impaired cell fitness of *NUP98* rearrangements |
| Menin + KAT6A/7 Inhibition | Significantly improved survival, effective in resistant cells |
Implications for Future Treatment Strategies
These findings suggest that targeting the assembly of proteins that drive leukemia through *NUP98* fusions could be a novel therapeutic vulnerability in AML. The study provides a strong rationale for evaluating this combination approach clinically, particularly in patients whose cancer is resistant to menin inhibition.
“We found *NUP98* fusions drive leukemia by assembling these proteins in a complex to switch on the expression of genes that turn normal cells into leukemia cells,” Dr. Mullighan explained. “We showed these inhibitors can stop the assembly of the switch, preventing activation of these cancer-driving genes, which may be a novel therapeutic vulnerability in AML.”
The Leukemia & Lymphoma Society reports that significant progress has been made in understanding and treating AML, but further research is needed to improve outcomes, especially for high-risk patients [2].
Evergreen insights: Understanding Pediatric AML
Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow. In pediatric AML, the disease develops in children and adolescents. *NUP98*-rearranged AML is a specific subtype characterized by fusions involving the *NUP98* gene, leading to the production of abnormal proteins that drive the development of leukemia. These rearrangements disrupt normal cellular processes, causing uncontrolled growth of myeloid cells.
Conventional treatments for pediatric AML include chemotherapy and stem cell transplantation. Though, *NUP98*-rearranged AML frequently enough presents a challenge due to its aggressive nature and potential for relapse. The identification of novel therapeutic targets, such as menin and KAT6A/7, offers hope for improving outcomes in these high-risk patients.
Frequently Asked Questions About *NUP98*-Rearranged Pediatric AML
What are the symptoms of pediatric AML?
Symptoms can include fatigue, fever, frequent infections, easy bruising or bleeding, bone pain, and swollen gums.
How is pediatric AML diagnosed?
Diagnosis typically involves a physical exam, blood tests, and a bone marrow biopsy to identify leukemia cells.
What are the treatment options for pediatric AML?
Treatment options include chemotherapy, radiation therapy, and stem cell transplantation. Targeted therapies are also being explored.
what is the prognosis for pediatric AML?
The prognosis varies depending on the subtype of AML, the patient’s age and overall health, and the response to treatment. *NUP98*-rearranged AML is often associated with a poorer prognosis.
Are there any long-term side effects of AML treatment?
Yes, long-term side effects can include growth problems, learning difficulties, infertility, and an increased risk of developing other cancers.
What are your thoughts on this potential breakthrough in pediatric AML treatment? How can we accelerate the development of new targeted therapies for childhood cancers?
Disclaimer: This article provides information for general knowledge and awareness only. It does not constitute medical advice and should not be substituted for professional consultation with a qualified healthcare provider.
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