Researchers at NYU Langone Medical Center and elsewhere say that blocking the action of an enzyme “switch” needed to activate tumor growth is emerging as a practical strategy for treating T-cell acute lymphoblastic leukemia.
An estimated quarter of the 500 U.S. adolescents and young adults diagnosed each year with this aggressive disease fail to respond to standard chemotherapy drugs that target cancer cells.
In a report on the work conducted with mice and human laboratory cells, and published in the Oct. 23 edition of the journal Nature, the NYU Langone team concludes that the enzyme JMJD3 — (pronounced ju-mon-ji D3) — acts as a cancer “on” switch by splitting off a chemical methyl group of another protein that is usually methylated by a tumor-suppressing enzyme. This enzyme, known as polycomb repressive complex 2 (PRC2), acts, in turn, as an “off” switch for cancer cell proliferation.
It is this destabilizing and cutting loose of PRC2, the same researchers previously showed, that leads to the activation of the NOTCH1 biological pathway – a process common to many cancers but especially active in at least half of all people with T-cell acute lymphoblastic leukemia.
“Our investigations are showing incredible promise in fighting this disease at the transcriptional level,” says senior study investigator and NYU Langone cancer biologist Iannis Aifantis, PhD. “We are blocking the action of enzymes controlling the transcription of proteins involved in leukemia rather than attempting to directly suppress cancer genes.”
The researchers say that the drug manufacturer, GlaxoSmithKline, is already developing an investigational compound called GSKJ4, whose treatment path follows the biological road map revealed in the new research. If GSKJ4works in further tests to prevent JMJD3 from destabilizing and evicting PRC2, Aifantis says, it could become the first of its kind alternative to standard chemotherapy in decades for treating this form of leukemia.
“Revealing the actions of JMJD3, and successfully blocking the enzyme to stall tumor progression, shows that new treatments for T-cell acute lymphoblastic leukemia are not simply theoretical, but practical,” adds Aifantis, chair of the Department of Pathology at NYU Langone and its Laura and Isaac Perlmutter Cancer Center, and an early career scientist at the Howard Hughes Medical Institute.
Aifantis says the latest findings are the culmination of several years of research by his team to unravel precisely how PRC2 suppresses tumor growth since they first reported the phenomenon in leukemia (Nature Medicine in 2012.) For the current study, they investigated precisely how demethylation —removal of a methyl chemical bond — triggers the chain of events that evicts PRC2 from cells, thereby removing PRC2 suppression of NOTCH1, which directly binds to and activates cancer-causing genes.
Specifically, they focused on a protein controlled and methylated by PRC2 called histone 3 lysine 27 (H3K27) as well as two other enzymes closely tied to H3K27 — JMJD3, and UTX, the latter short for ubiquitously transcribed tetratricopeptide repeat X-linked protein.
What the study found is that JMJD3 was highly active in both mice and human leukemia cells at all stages of tumor growth and development. By contrast, UTX was not overly produced in leukemia, but highly active in noncancerous mouse and human cells. When mice and human leukemia cells were treated with the experimental drug GSKJ4, JMJD3 activity stopped and all cancer cells eventually died, the researchers report.
Subsequent genetic experiments showed that in leukemic mice bred so they are unable to make JMJD3, NOTCH1 activity declined, while UTX activity remained the same. The disease also progressed much faster, they found, in mice bred without UTX, while mice lived longer if they produced UTX. The findings suggest that UTX production controls several tumor-suppressing genes.
To further confirm their findings, researchers screened more than 200 blood samples from children and adults with T-cell acute lymphoblastic leukemia, revealing several common mutations in UTX.
Plans are underway, Aifantis says, to test GSKJ4 against human leukemia cells transplanted into mice. Other experiments will use the drug molecule in combination with standard chemotherapy in animals with leukemia.
“Our report serves as a valuable reminder of just how complex cancers like T-cell acute lymphoblastic leukemia can be, and that enzymes can play many, even opposing, roles in both tumor growth and suppression,” says Aifantis.
Funding support for the study was provided by the U.S. National Cancer Institute and National Institute of General Medical Sciences, both parts of the National Institutes of Health. Corresponding federal grant numbers are P30 CA016087-30, P30 CA016087-31, R01 CA133379, RO1 CA105129, R01 CA149655, R01 CA173636, R01 169784, R01 CA120196, R37 HD04502, T32-CA009161-37, U24 CA114737, and K99 CA 188293. Further funding support was provided by the William Lawrence and Blanche Hughes Foundation, the Leukemia and Lymphoma Society (corresponding grant numbers TRP#6340 -11 and LLS#6373-13), the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick’s Foundation, the Lady Tata Memorial Trust for Leukemia, and the American Society of Hematology.
Besides Aifantis, other NYU Langone researchers involved in these experiments were lead study investigator Panagiotis Ntziachristos, PhD, and study co-investigators Aristotelis Tsirigos, PhD; Thomas Trimarchi, BSc; Sofia Bakogianni, BSc; Evangelia Loizou, MS; Alexandros Strikoudis, BSc; Bryan King, PhD; Jasper Mullanders, PhD; and Jelena Nedjic, PhD. Additional research support was provided by Grant Welstead, and Rudolf Jaenisch, at the Massachusetts Institute of Technology in Boston; Luyao Xu, Pieter Van Vlierberghe, and Adolfo Ferrando, at Columbia University in New York; Linda Holmfeldt, PhD; Jared Becksfort; and Charles Mullighan, MD, PhD, at St. Jude Children’s Research Hospital in Memphis, Tenn.; Elisabeth Paietta, at Montefiore Medical Center North in New York; Martin Tallman, at Memorial Sloan-Kettering Cancer Center in New York; Jacob Rowe, at Technion Israel Institute of Technology in Haifa; Giovanni Tonon, at the San Raffaele Scientific Institute in Milan, Italy; Takashi Satoh, and Shizuo Akira, at Osaka University in Japan; Laurens Kruidenier and Rab Prinjha, at GlaxoSmithKline in Stevenage, United Kingdom.
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