Researchers discover an Achilles heel in a lethal leukemia

November 16, 2017, St. Jude Children's Research Hospital
Researchers discover an Achilles heel in a lethal leukemia
(From left) John Schuetz, Ph.D., and first author Aaron Pitre, Ph.D., screened thousands of compounds to identify those that could disrupt the ABCC4-MPP1 connection. This disruption caused cells to become more sensitive to drugs used in AML treatment.  Credit: St. Jude Children's Research Hospital

Researchers have discovered how a linkage between two proteins in acute myeloid leukemia enables cancer cells to resist chemotherapy and showed that disrupting the linkage could render the cells vulnerable to treatment. St. Jude Children's Research Hospital scientists led the research, which could lead to drugs to enhance chemotherapy in patients with AML, colon and breast cancers and the brain tumor medulloblastoma.

New treatments for AML are critical because overall five-year survival for adults and children with this leukemia is about 27 percent.  John Schuetz, Ph.D., a member of the St. Jude Department of Pharmaceutical Sciences, led the research, which appears today in the scientific journal Nature Communications.

The investigators launched their experiments based on findings from other scientists that a called ABCC4 was greatly elevated in aggressive cases of AML. Schuetz and his colleagues searched for other proteins that might interact with ABCC4 and enable its function. Their screening of hundreds of candidate proteins yielded one, MPP1, which was also greatly increased in AML.

The researchers showed that the two proteins were connected and that the connection enabled cells to assume the characteristics of highly proliferative leukemia cells. These experiments involved genetically altering blood-forming blood progenitor cells to have high MPP1 and ABCC4 levels. The cells were grown in culture and then transferred, or replated, to new culture dishes to see if the cells would continue to grow. Such self-renewal is a hallmark of leukemia cells. The researchers found that serial regrowth depended on the cells having high levels of both ABCC4 and MPP1.

"Typically if you take normal progenitors and you replate, you could do that one time, maybe twice," Schuetz said. "But our big surprise was that overexpressing MPP1—analogous to what you would see in leukemia—allows those progenitors to self-renew, to be replated over and over, to form new colonies."

The experiments also revealed that the two proteins functioned at the cell membrane, where they could play a role in the machinery that would rid the of drugs.

 "When we disrupted their interaction, ABCC4 moved off the membrane and the cells became more sensitive to drugs used in AML—drugs that are pumped out of the cell by ABCC4," Schuetz said.

By screening thousands of compounds, the researchers identified those that could disrupt the ABCC4-MPP1 connection. One, called Antimycin-A, reversed resistance in AML cell lines and in from AML patients. Antimycin-A is too toxic to be used in chemotherapy, but identification of the compound should help scientists searching for other, less-toxic drugs to disrupt the ABCC4-MPP1 interaction.

The findings could also enable clinicians to identify AML patients with high levels of ABCC4 and MPP1. Such patients might benefit from drugs that disrupt ABCC4-MPP1 by enhancing the effectiveness of standard chemotherapy, Schuetz said. Also, he noted, other cancers including breast and colon and medulloblastoma show high levels of both ABCC4 and MPP1. Chemotherapy for those cancers might also be enhanced by drugs that disrupt ABCC4-MPP1.

Explore further: Discovery points to drugs that would 'short-circuit' deadly leukemia

More information: Aaron Pitre et al. An unexpected protein interaction promotes drug resistance in leukemia, Nature Communications (2017). DOI: 10.1038/s41467-017-01678-y

Related Stories

Discovery points to drugs that would 'short-circuit' deadly leukemia

August 3, 2017
Researchers at St. Jude Children's Research Hospital have discovered that survival of a particularly aggressive form of acute myeloid leukemia (AML) depends on production of a small molecule called heme that is a kind of ...

Fat cells may inactivate chemotherapeutic drug

November 8, 2017
Adipocytes, or fat cells, can absorb and metabolize the chemotherapeutic agent daunorubicin, reducing the effectiveness of the drug and potentially contributing to poorer treatment outcomes.

How cells detect, mend DNA damage may improve chemotherapy

November 8, 2017
The busy world inside a cell is directed by its DNA blueprint. When the blueprints are altered, cells can sicken, die or become cancerous. To keep DNA in working order, cells have ways to detect and mend damaged DNA.

Technique identifies chemotherapy-resistant cells within acute myeloid leukemia tumors

September 6, 2016
Although chemotherapy can sometimes cure acute myeloid leukemia and other hematologic cancers, many patients experience relapses when their tumors become resistant to available chemotherapies. This resistance may be caused ...

Genetic targets to chemo-resistant breast cancer identified

October 3, 2017
Research led by Dr. Carlos Arteaga, Director of the Harold C. Simmons Comprehensive Cancer Center, has identified potential targets for treatment of triple negative breast cancer, the most aggressive form of breast cancer.

Screening drugs to kill cancer cells in their safe spaces

October 31, 2016
Existing chemotherapy approaches treat cancer by targeting cells that are actively multiplying and have a high metabolic rate. However, cancer stem cells can escape this targeting, leading to chemotherapy-resistant cancer ...

Recommended for you

'Embattled' breast cancer drugs could be revived by new discovery

June 25, 2018
More than 60 percent of breast cancer cases involve defects in the same biochemical chain of events within cancer cells—known as the PI3 kinase (PI3K) pathway—but efforts to develop therapies targeting this pathway have ...

Immune profile for successful cancer immunotherapy discovered

June 25, 2018
In a new study published online June 25, 2018 in Nature Medicine, UC San Francisco researchers have identified a key biological pathway in human cancer patients that appears to prime the immune system for a successful response ...

A new tactic for starving tumors

June 25, 2018
A tumor's goal is simple: to grow, grow, grow, by making more cancer cells. But that often means growing so fast that the oxygen supply gets scarce, at which point cells within the tumor start to suffocate. Without oxygen, ...

Lethal prostate cancer treatment may benefit from combination immunotherapy

June 25, 2018
Researchers at the Johns Hopkins Kimmel Cancer Center and the Bloomberg~Kimmel Institute for Cancer Immunotherapy (BKI) released a study investigating the use of combination checkpoint immunotherapy in the treatment of a ...

New drugs are improving survival times for patients with aggressive type of blood cancer, study finds

June 25, 2018
Survival times for a highly aggressive type of blood cancer have nearly doubled over the last decade due to the introduction of new targeted drugs, a Yorkshire study has shown.

Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant

June 21, 2018
A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.