Acute Myeloid Leukemia (AML) grows by taking advantage of the B6 vitamin to accelerate cell division

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Scientists have discovered that Acute Myeloid Leukemia (AML) grows by taking advantage of the B6 vitamin to accelerate cell division.

The research team from Cold Spring Harbor Laboratory (CSHL) and Memorial Sloan Kettering Cancer Center (MSK) suggest they could halt the growth of this cancer by limiting its ability to manipulate the enzyme that pushes B6 to make proteins essential for cell division.

It’s an approach to attacking cancer without harming healthy cells, which need the B6 vitamin to survive.

Currently, only one-third of AML patients will survive five years after diagnosis. That’s because, like many other deadly cancers, the cells involved in this aggressive form of blood cancer can divide and spread faster than most treatments can kill them.

CSHL Fellow Lingbo Zhang wanted to know how AML can achieve such rapid growth, so he looked closely at the genes of the disease’s cancerous white blood cells.

“We found more than 230 genes that are very active in leukemic cells and then we tested them, one by one,” he explained.

Using CRISPR gene-editing technology, Zhang’s lab shut down the activity of each of these 230 suspect genes to see if their absence would stop the cancer cells from proliferating.

Among the hundreds of genes they tested, one pattern emerged. The gene which produces PDXK, the enzyme that helps cells use vitamin B6, proved most important for the growth of the cancer.

Scott Lowe, a former CSHL fellow and currently the chair of the Cancer Biology and Genetics program at MSK, said “while the action of certain vitamins has previously been linked to cancer, the specific links between vitamin B6 identified here were unexpected.”

The B6 vitamin is crucial to cell metabolism, producing energy and other resources important for cell growth. In a healthy cell, the PDXK enzyme manages the activity of B6, making sure that the vitamin does the job when needed. Because normal cells don’t actually divide all the time, the PDXK enzyme isn’t always pushing the B6 vitamin to be active.

It’s a different dynamic in cancer cells, which divide more frequently than normal cells. In AML cells, Zhang saw that the PDXK enzyme was always pushing B6 activity.

What this shows is that, “leukemic cells are addicted to vitamin B6,” he said. “You can call it a vulnerability of the cancer.”

Zhang cautions that his research on how cancer cells use the B6 vitamin to proliferate does not mean that cancer patients would necessarily benefit from reduced intake of B6 vitamin as part of their diet.

The B6 vitamin is necessary for the survival of healthy cells. Zhang’s research shows that cancer cells take advantage of the PDXK enzyme to increase B6 vitamin activity.

This increased activity fuels AML growth.

Zhang and his colleagues say the next step is to develop a drug that specifically blocks leukemia from activating the PDXK enzyme.

By manipulating the way the enzyme manages the activity of B6, a drug could slow or even stop the growth of cancerous cells without the profound side effects that would result from completely eliminating B6 from healthy cells. With the help of medicinal chemists, the team is now exploring this route.


Acute lymphoblastic leukemia (ALL) accounts for approximately one fourth of all childhood malignancies [1]. Cure rates now exceed 90%, which allows a growing number of childhood survivors to reach adulthood [1]. However, survivors may face severe long-term sequelae years after the end of treatments [2,3].

In particular, studies on childhood ALL (cALL) survivors have reported a high prevalence of the typical components of the metabolic syndrome, namely obesity [4], hypertension [5], glucose intolerance [6] and dyslipidemia [7].

It is important to note that cALL survivors are at higher risk of developing low levels of HDL-C [8–10]. Alterations in HDL particle composition in lipids and proteins were also found in this population [11,12], suggesting defects in functionality. HDL particles are known for their ability to promote reverse cholesterol transport, but their functions are more extensive in view of their anti-atherosclerotic properties such as antioxidant [13,14], anti-apoptotic [15], anti-inflammatory [16], anti-hypertensive [17] and anti-thrombotic [18] roles.

In the general population, a typical Western dietary pattern, characterized by a higher consumption of fried foods and sweetened beverages, was associated with the incidence of the metabolic syndrome components and of atherosclerosis [19–21].

Conversely, plant-based diets and whole grains can be protective against insulin resistance, dyslipidemia and hypertension [22–26]. Similarly, several key micronutrients (polyphenols, vitamins and minerals: e.g., vitamins A, C, E and selenium) exhibited anti-inflammatory and antioxidative properties [22,27]. Moreover, like the general population, cALL survivors do not respect dietary guidelines [28,29].

Thus, one can understand the relationship between inadequate nutrition and the increased risk of developing long-term sequelae by cALL survivors [28,30,31], whereas the inclusion of specific nutrients or dietary patterns was found to be protective [30,31]. In cALL survivors, greater adherence to a Mediterranean diet was associated with lower visceral adiposity, subcutaneous adiposity, waist circumference, and BMI [30].

Likewise, lower dietary quality, measured with the Healthy Eating Index-2005, was associated with higher body fat in survivors of childhood cancer [31].

Adherence to a Mediterranean diet improves HDL efflux capacity, antioxidative status and vasoprotective capacity in the general population [32]. In addition, associations were found between intake of folate and magnesium and HDL-C, HDL2, HDL3 and apolipoprotein (Apo)-AI [33].

However, the influence of dietary intakes on HDL-C levels in cALL survivors remains unknown. The major aim of this study was to study the associations between macro/micronutrient intake and the presence of low HDL-C in the PETALE cohort comprising of children and young adult survivors of cALL in the Province of Quebec, Canada.

Conclusions

Our study supports a potential beneficial effect of dietary proteins, meat, selenium, zinc, copper, riboflavin, and niacin and a deleterious effect of fast food on HDL-C in cALL survivors.

This preliminary groundwork provides fundamentals that contribute to our understanding of the role of nutrition in the development of dyslipidemia in this population. Based on these results, we propose that a diet rich in high-quality lean proteins and in key micronutrients could contribute to protect cALL survivors against having low HDL-C.

This study emphasizes the role of nutrition in the development of dyslipidemia after cancer treatment. Nutritional strategies could be a valuable approach to preventing long-term cardiometabolic complications in cALL survivors.

Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6643/11/12/2977/s1, Table S1: Cut-off values for cardiometabolic outcomes, Table S2: Classification of food groups, Table S3: Calculation of Estimated Energy Requirement


More information: Chen et al, Vitamin B6 addiction in acute myeloid leukemia, Cancer Cell, January 13, 2020. DOI: 10.1016/j.ccell.2019.12.002

Journal information:Cancer Cell

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