Monday, December 2, 2019

CHILDREN AND LEUKEMIA - Leukemia, which disrupts normal cell growth in the blood and bone marrow, accounts for nearly one-third of all childhood cancer cases. Certain forms of leukemia tend to strike early in life and affect far more children than adults. The disease manifests in various forms, and the subtypes that mostly affect children typically progress quickly and require immediate, aggressive treatment. Although similarities exist between childhood and adult leukemias, evidence suggests that the cancers don't share the same genetic roots. What has been known for some time is that there are clear genetic differences between childhood cancer and adult cancer. Important distinctions between childhood and adult leukemia may lie in how the bone marrow functions in people of different ages and how cancer commandeers that tissue for its own purposes.

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Children And Leukemia
Why Do Some Forms of Leukemia Affect Mostly Children?
By Nicoletta Lanese - Staff Writer 




Childhood leukemias may exploit specific vulnerabilities found only in immature cells.
Certain forms of leukemia tend to strike early in life and affect far more children than adults.          
Leukemia, which disrupts normal cell growth in the blood and bone marrow, accounts for nearly one-third of all childhood cancer cases, according to the American Cancer Society (ACS).
The disease manifests in various forms, and the subtypes that mostly affect children typically progress quickly and require immediate, aggressive treatment.
Although similarities exist between childhood and adult leukemias, evidence suggests that the cancers don't share the same genetic roots.                   
"What has been known for some time is that there are clear genetic differences between childhood cancer and adult cancer," said Dr. Thomas Mercher, a director of hematology-oncology research for the French National Institute of Health and Medical Research and the Gustave Roussy research institute in Villejuif, France.
Studies suggest that the specific genetic quirks seen in childhood leukemia cells may arise very early in life, or even in the womb, but how this happens step by step "is generally very unclear," Mercher said. 
Now, new research hints that childhood leukemia may be able to hijack only young, developing cells — like those found in fetuses and children — not the mature cells of full-grown adults. 
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To investigate why certain leukemias may prey on immature cells, Mercher and his colleagues gathered genetic samples from young patients with a particularly aggressive form of acute myeloid leukemia (AML) and replicated the disease in mouse models.
The team's study, published Oct. 29 in the journal Cancer Discovery, hints at why the cancer appears early in life, often before the affected child reaches 2 years old.
"The genetic alterations that we studied here are only found in childhood leukemia," Mercher added. 
In general, AML is more prevalent in adults than children; the disease accounts for fewer than 25% of all childhood leukemia cases, according to the American Cancer Society.
However, a rare subtype called "acute myeloblastic leukemia type 7" (AML-M7) predominantly appears in infants under the age of 2.
Children with other forms of AML develop the disease later in life, around age 6, and show better survival rates than individuals with the more-aggressive subtype, the authors noted in a statement
Could the children's ages at the time of disease onset offer clues as to why these cancers have such different outcomes? To find out, the researchers looked to the children's genes.     
Frankenstein-style mutations 
Back in 2012, the team gathered leukemia cells from both children and adults who had AML-M7, discovering a key difference between the genetic material in the children versus the adults.
Many of the children's cells contained genes that had merged together, Frankenstein-style, to form new, hybrid genes.
Individually, the genes play important roles in blood cell development, but once stuck together, those genes may direct cells to build unusual proteins and ultimately transform into cancerous cells, the researchers theorized.
None of these "fusion genes" appeared in a single adult leukemia cell, which hinted that the team might be onto something.      
After the researchers published this initial finding, they and other scientists found ample evidence of fusion genes in AML-M7 leukemia.
But no one knew exactly what these hybrid genes did or why they appeared only in children. 
So, Mercher and his colleagues continued to investigate, focusing their research on a fusion gene known as ETO2–GLIS2.
Welding together two normally separate genes, ETO2 and GLIS2, the mutation appears in about 30% of children with AML-M7 and seems linked to poor responses to cancer treatment and low survival rates, the researchers wrote.
To learn how this mutation drives cancer, the team observed how the fusion gene seized control of hematopoietic stem cells, cells that normally give rise to healthy blood cells but can get hijacked by leukemia.          
The scientists developed a mouse model in which they could turn the ETO2–GLIS2 mutation "on" or "off" in a given tissue inside the mouse.
They ran their experiment in both fetal and adult-age mice to see if the fusion gene would affect cells differently depending on the cells' stage of development.
Turns out, that's exactly what happened. When the team activated ETO2–GLIS2 in fetal stem cells, the resulting proteins seemed to tamper with cellular pathways that normally turn the cells into healthy blood cells.
Basically, the fusion gene flipped a "molecular switch" that rapidly transformed the stem cells into aggressive leukemia.
Blocking ETO2–GLIS2 activation in the same fetal mice flipped the switch back, curbed the cancer growth and allowed stem cells to turn into normal blood once more. 
By comparison, the adult stem cells appeared "much less prone to give rise to leukemia" when ETO2–GLIS2 was activated, Mercher said.
In fact, the fusion gene did not appear to be a key driver of leukemia progression in adult mice. 
"The developmental stage of the cells in which the mutation arises determines the aggressiveness and the type of leukemia that you get," Mercher said. 
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The results "show that more people should be paying attention to the fetal bone marrow environment," where hematopoietic stem cells can be found, said Dr. Mignon Loh, a pediatric hematologist-oncologist at the University of California, San Francisco, who was not involved in the study.
The immediate environment, or niche, where a fetal stem cell develops looks very different from the environment surrounding an adult cell, she said. 
"When you're a baby and have been incubating for 9 months, that niche is pretty pure," Loh said. Important distinctions between childhood and adult leukemia may lie in how the bone marrow functions in people of different ages and how cancer commandeers that tissue for its own purposes, she said. 
Research into ETO2–GLIS2 may also shed light on how other forms of childhood leukemia rely on fusion genes, provided that the team's findings in mice hold true in humans, Loh said.
More broadly, further research into the nature of fetal stem cells in general could reveal other avenues by which leukemia exploits developing cells, she said.
"There may be something permissive about a fetal-like stem cell" that allows it to transform into malignant cancer, Loh said.
If future research could pinpoint how child-specific mutations cause leukemia, drugs could be developed to stall or stop the disease, Mercher added. 
"That would be like [finding] the holy grail," Loh said.

Nicoletta Lanese is a science journalist and dancer who aims to bring science to new audiences, whether in print or on stage. She holds degrees in neuroscience and dance from the University of Florida and a graduate certificate in science communication from the University of California, Santa Cruz. Brains are her beat. Follow her on Twitter @NicolettaML. 
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