Fighting leukemia by targeting a little-known protein

AML
The protein SCP4 could point to a potential new approach for treating acute myeloid leukemia, scientists at Cold Spring Harbor Laboratory found. (National Cancer Institute)

Proteins known as phosphatases are essential to myriad cellular signaling pathways, including those that drive cancer. A research team led by scientists at Cold Spring Harbor Laboratory have just pinpointed a little-known phosphatase that acute myeloid leukemia (AML) cells appear to rely on for survival.

Phosphatase SCP4, by working with two protein kinases, is essential in AML proliferation, but it seems dispensable to normal blood stem cells, the team reported in a study published in the journal Cell Reports.

While kinase-targeting drugs have been widely used to fight cancers, including AML, this new finding points to a potential new approach, the researchers said.

Phosphatases and kinases work hand in hand in regulating cell activities. In a mechanism behind a wide spectrum of cellular processes, a kinase adds a phosphate group onto other protein substrates and a phosphatase takes them off.

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In the current study, researchers used CRISPR-Cas9 genetic screening to identify phosphatases that AML depends on for survival in cell cultures. Of all the 217 phosphatase domains, 11 returned as essential across the entire panel of cell lines tested. Among them, SCP4 ranked at the top for AML dependency.

AML is rooted in an abnormal transformation of stem-cell-like hematopoietic progenitor cells. Crippling SCP4 in normal hematopoietic progenitor cells didn’t affect cell fitness in lab dishes or cause any notable problem for blood formation in young mice, the researchers found.

As part of their analysis to better understand SCP4's mechanism, the scientists found the phosphatase acts through two little-studied kinases, STK35 and PDIK1L.

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In the search for other novel approaches against AML, researchers at the Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow recently found that combined inhibition of MDM2 and BET could better activate the tumor-suppressing protein p53 than each drug alone did.

Also using CRISPR screening for clues, a team at the University of Pennsylvania showed that inhibiting a protein called ZMYND8, which can recognize epigenetic changes and influence gene expression involved in cancer's spread through the body, could block AML growth in mice.

Protein kinase inhibitors are among the most popular types of cancer drugs. For AML alone, the FDA has approved inhibitors of the FLT3 kinase such as Astellas’ Xospata and Novartis’ Rydapt.

The Cold Spring Harbor-led team now believes that SCP4 and its phosphatase-kinase signaling complex with STK35 and PDIK1L might offer a new therapeutic opportunity against AML.