Study of the Week: Scientists Discover NPM1-Mutated AML Subtypes

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Biological and therapeutic implications of a unique subtype of NPM1 mutated AML

We previously published about this research in a story titled “One Treatable, One Untreatable: These Oncologists Find Two Subtypes of AML,” which can be found here. The study was originally published in the research journal Nature Communications. You can view the fully study text here.

What Happened?

Cancer is a complex and varied disease that often displays great molecular and genetic variability. This has spurred a push towards genetic testing in cancer patients and a greater understanding of the need for a personalized treatment course based on test results. Acute myeloid leukemia (AML) has different variants as well; one example that is often seen is NPM1-mutated AML. Mutations affecting the NPM1 gene appear in up to 30 percent of AML cases. Overall, the NPM1 mutation is considered an indicator of favorable prognosis compared to other variants of AML.

With that being said, patients with this mutation see relapse occur around 40 percent of the time. Since some patients with this mutation seemed to respond better to treatment than others, the scientists sought to further investigate the NPM1 mutations to see if they could find an explanation. Using analysis of gene expression, immunophenotyping, and the epigenome, that researchers identified two distinct subtypes of NPM1-mutated AML, which they label as ‘primitive’ and ‘committed.’

This study used five different cohorts of AML patients. In the primitive subtype, the researchers found that the hedgehog-interacting protein (HHIP) gene was upregulated. This subtype was also associated with the FLT3-ITD mutation. While the mutation was not actually present in 36 percent of the primitive samples, the transcriptomic profile was still extremely similar.

In the committed subtype, the CD14 and CD163 genes were upregulated instead. The committed subtype also had more advanced myelomonocytic differentiation. This subtype was also associated with mutations of the NRAS and FLT3-TKD genes. 29 percent of the committed subtype samples saw a gene expression pattern similar to wild type FLT3 yet contained the FLT3-ITD mutation.

About Acute Myeloid Leukemia (AML)

Acute myeloid leukemia, also known as acute myelogenous leukemia, is a type of blood cancer which affects myeloblasts, stem cells that would normally develop into myeloid white blood cells. There are a number of risk factors for acute myeloid leukemia, including other blood disorders such as myelodysplastic syndrome, family history, certain genetic variants, chemical exposure (including chemotherapy agents), and radiation. Symptoms include an increased risk of infection, easy bruising and bleeding, fatigue, shortness of breath, fever, weight and appetite loss, anemia, and bone/joint pain. Treatment for this cancer is most often chemotherapy or stem cell transplant; there are very limited options for patients with relapsed disease. The five year survival rate for acute myeloid leukemia is only 27 percent in the US. There is a clear need for more effective treatments for this cancer. To learn more about acute myeloid leukemia, click here.

Why Does it Matter?

The results of this study have revealed critical information about NPM1-mutated AML. The genetic differences between the primitive and committed subtypes are important. Overall, the primitive subtype is less likely to respond effectively to treatment in comparison to the committed subtype. The FLT3-ITD mutation is of particular concern when found alongside NPM1 as this mutation is associated with a lowered chance of remission with chemotherapy and 70 percent relapse risk. 

The relapse risk is around 40 percent for NPM1 patients with FLT3 wild type, yet 37 percent of the wild type samples fell under the primitive subtype. All of these different subtypes, mutations, and variants may sound confusing, but it is clear that understanding each patient’s individual cancer characteristics can be important predictors of treatment outcomes. More targeted therapies based on the newly discovered primitive and committed subtypes could play a major role in improving future treatment.

The researchers have already compiled a list of therapies that could have the potential to benefit patients with these two subtypes, and it is possible that drugs used to treat other types if cancer could make a difference for these patients. Two drugs were found to effectively target the primitive subtype in the lab setting, providing a potential basis for a future trials. Overall, identifying these distinctions in AML are critical for bettering the lives of patients.

Check back the Monday of each week for the next installment in this series.

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