Blocking Enzyme Switch Turns Off Tumor Growth in T-Cell Acute Lymphoblastic Leukemia

In a report on the research with mice and human laboratory cells, which was published in the October 23, 2014, edition of the journal Nature, investigators from New York University (NYU) Langone Medical Center (New York, NY, USA) concluded that the enzyme JMJD3 acts as a cancer “on” switch by splitting off a 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, to inactivate cancer cell proliferation.

The destabilizing and getting rid of PRC2, as the same researchers previously revealed, leads to the activation of the NOTCH1 biologic pathway, a process common to many cancers but particularly active in at least 50% of all individuals 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 noted that the drug manufacturer, GlaxoSmithKline (Middlesex, UK), is already developing an investigational compound called GSKJ4, whose treatment path follows the biologic blue print revealed in the new research. If GSKJ4 works in further testing to prevent JMJD3 from destabilizing and expelling PRC2, Dr. Aifantis noted, it could become the first of its kind option to standard chemotherapy in years for treating this type 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,” added Dr. Aifantis, chair of the department of pathology at NYU Langone.

Dr. Aifantis reported that the latest findings are the culmination of several years of research by his team to unravel precisely how PRC2 inhibits tumor growth since the investigators first reported the phenomenon in leukemia published in 2012 in the journal Nature Medicine. For this study, the researchers investigated exactly how demethylation, the 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, the researchers 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 blocked and all cancer cells ultimately died, the researchers reported.

Subsequent genetic research showed that in leukemic mice bred so that they are unable to make JMJD3, NOTCH1 activity dropped, while UTX activity remained the same. The disease also progressed much faster, the investigators discovered, 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 additionally validate the 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 ongoing, according to Dr. Aifantis, to assess GSKJ4 against human leukemia cells transplanted into mice. Other research will use the drug molecule in combination with standard chemotherapy in animal models 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,” concluded Dr. Aifantis.

Related Links:
New York University Langone Medical Center
GlaxoSmithKline