Certain DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells, cancer researchers have found.
Many cancer-driving mutations are “cell-autonomous,” meaning the change in a cell’s DNA makes that same cell grow more rapidly. In contrast, an indirect neighbor cell effect was observed in a mouse model of Noonan syndrome, an inherited disorder that increases the risk of developing leukemia.
In mouse bone marrow, mesenchymal stem cells (red), which normally nurture blood stem cells, produce a signal that is attractive for monocytes. The monocytes (green) prod nearby blood stem cells to proliferate, leading to leukemia. From Dong et al Nature (2016).
The findings were published Wednesday, October 26 in Nature.
The neighbor cell effect could be frustrating efforts to treat leukemias in patients with Noonan syndrome and a related condition, juvenile myelomonocytic leukemia (JMML). That’s because bone marrow transplant may remove the cancerous cells, but not the cause of the problem, leading to disease recurrence. However, the researchers show that a class of drugs can dampen the cancer-driving neighbor effect in mice. One of the drugs, maraviroc, is already FDA-approved against HIV infection.
“Our research highlights the importance of the bone marrow microenvironment,” says Cheng-Kui Qu, MD, PhD, professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta. “We found that a disease-associated mutation, which disturbs the niches where blood stem cell development occurs, can lead to leukemia formation.”
Editorial note: This Nature News + Views, aptly titled “Bad neighbors cause bad blood,” explains JMML, and how the relapse rate after bone marrow transplant is high (about 50 percent). It also notes that a variety of genetic alterations provoke leukemia when engineered into bone marrow stromal cells in mice (like this), but Qu and his colleagues described one that is associated with a known human disease.
Noonan syndrome often involves short stature, distinctive facial features, congenital heart defects and bleeding problems. It occurs in between one in 1000 to one in 2500 people, and can be caused by mutations in several genes. The most common cause is mutations in the gene PTPN11. Children with Noonan syndrome are estimated to have a risk of developing leukemia or other cancers that is eight times higher than their peers. Read more
Scientists at Winship Cancer Institute, Emory University have identified compounds that stop two elusive anticancer targets from working together. In addition to striking two birds with one stone, this research could expand the envelope of what is considered “druggable.”
Many of the proteins and genes that have critical roles in cancer cell growth and survival have been conventionally thought of as undruggable. That’s because they’re inside the cell and aren’t enzymes, for which chemists have well-developed sabotage strategies.
In a twist, the potential anticancer drugs described in Cancer Celldisable an interaction between a notorious cancer-driving protein, MDM2, and a RNA encoding a radiation-resistance factor, XIAP.
The compounds could be effective against several types of cancer, says senior author Muxiang Zhou, MD, professor of pediatrics (hematology/oncology) at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center.
In the paper, the compounds show activity against leukemia and neuroblastoma cells in culture and in mice, but a fraction of many other cancers, such as breast cancers (15 percent) and sarcoma (20 percent), show high levels of MDM2 and should be susceptible to them.
Graft-vs-host disease is a common and potentially deadly complication following bone marrow transplants, in which immune cells from the donated bone marrow attack the recipientâ€™s body.
Winship Cancer Instituteâ€™s Ned Waller and researchers from Childrenâ€™s Healthcare of Atlanta and Yerkes National Primate Research Center were part of a recent Science Translational Medicine paper that draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease.
Aurora kinases are enzymes that control mitosis, the process of cell division, and were first discovered in the 1990s in yeast, flies and frogs. Now drugs that inhibit aurora kinase A are in clinical trials for several types of cancer, and clinicans are planning to examine whether the same type of drugs could help with graft-vs-host disease.
Leslie Kean, a pediatric cancer specialist at Seattle Childrenâ€™s who was at Emory until 2013, is the senior author of the STM paper. Seattle Childrens’ press releaseÂ says that Kean wears a bracelet around her badge from a pediatric patient cured of leukemia one year ago, but who is still in the hospital due to complications from graft-vs-host. Read more
Parietin, shown to have anticancer activity in the laboratory, is a dominant pigment in Caloplaca lichens. Note: this study did not assess the effects of eating lichens or rhubarb. Photo courtesy of www.aphotofungi.com
Parietin, also known as physcion, could slow the growth of and kill human leukemia cells obtained directly from patients, without obvious toxicity to human blood cells, the authors report. The pigment could also inhibit the growth of human cancer cell lines, derived from lung and head and neck tumors, when grafted into mice.
A team of researchers led by Jing Chen, PhD, discovered the properties of parietin because they were looking for inhibitors for the metabolic enzyme 6PGD (6-phosphogluconate dehydrogenase). 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. Researchers have already found 6PGD enzyme activity increased in several types of cancer cells.
“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” says Chen, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.” Read more
Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.
The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cellsÂ in vitro, but provides information on how to dose imatinib for new clinical applications.
â€œWe think that low doses of imatinib are mimicking â€˜emergency hematopoiesis,â€™ a normal early response to infection,â€ says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.
Imatinib, is an example of a â€œtargeted therapyâ€ against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.
Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens â€“ both bacteria and viruses â€“ exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, includingÂ tuberculosis bacteriaÂ andÂ Ebola virus. Read more
Before all the excitement about embryonic stem cells, doctors were using hematopoetic â€“ that is, blood-forming — stem cells. Hematopoetic stem cells can replenish all the types of cells in the blood, and are the centerpiece of transplantation as treatment for diseases such as multiple myeloma or leukemia. They can come from two different places: directly from the marrow of a donorâ€™s hip bone, or indirectly from the donorâ€™s blood after a drug nudges the stem cells out of the bone marrow.
Most hematopoetic stem cell transplants in the United States now use the indirect method of obtaining the stem cells. Until this fall, gold-standard randomized clinical trial results were not available to say which method is best for patient outcomes. Winship Cancer Institute hematologist Ned Waller was a key co-author of a study that was published in October in the New England Journal of Medicine addressing this question.
The trial involved 48 centers enrolling 551 patients as part of the Bone Marrow and Clinical Trials Network (BMT CTN).Â Waller helped design the study, and his lab at Winship analyzed the cells in each type of graft as the central core lab for the trial.
The study found no significant difference in the overall Ray Ban Italia survival rate at two years, and no difference in relapse rates or in acute graft-versus-host-disease (GVHD). However, there was a significantly higher rate of chronic GVHD with the use of blood stem cells.
GVHD, a difficult and sometimes life-threatening complication for this type of transplant, involves damage inflicted by the transplant recipientâ€™s new immune system upon the liver, skin and digestive system.
This finding will generate serious discussion among leaders in the transplant field about whether bone marrow or peripheral blood stem cell transplantation is a better treatment option, Waller says. A text Q + A with him follows.
What was surprising about the results of this study?
The equivalent survival was expected, and the increased chronic GvHD in recipients of blood stem cell grafts was suspected. What is surprising is that the relapse rate was similar between the two arms, in spite of the PBSC arm having more chronic GvHD.
The accompanying editorial argues bone marrow should be the standard for unrelated-donor transplants. Do you agree?
Yes, with the exceptions that Fred mentioned: patients with life-threatening infections and patients at high risk for graft rejection.
What are the differences, procedurally, between bone marrow and peripheral blood as sources for hematopoetic stem cell transplant?
Donating bone marrow involves a two or three hour surgical procedure requiring general anesthesia, in which bone marrow is removed from the hip bone with a needle and syringe.Â For peripheral blood stem cells, the donor undergoes five days of injections of granulocyte colony-stimulating factor and then a four-hour apheresis procedure to harvest stem cells from the blood. Blood stem cell donors have bone pain during the 5-day period of cytokine treatment, and bone marrow donors have more discomfort early after donation, but symptoms for both BM and PBSC donors have typically resolved by four weeks after donation.
What proportion of each is now in use here?
Marrow is the graft source in about 25% of recipients of grafts from unrelated donors, 10% in recipients of grafts from related donors.
What proportion of HSCT is unrelated donor?
For allogeneic transplants, about 60% receive grafts form unrelated donors (33% matched related donors and 7% mis-matched related donors).
What kind of information does this study provide oncologists/hematologists about which option to use in which situation?
Marrow should be preferred in recipients of grafts from unrelated donors when the conditioning regimen is myeloablative [substantially damages the patient’s existing bone marrow].
Does it depend on the type of leukemia/myeloma, the age or other conditions of the patient etc?
This study only enrolled patients with acute leukemia and MDS [myelodysplastic syndrome]. It excluded patients with myeloma or lymphoma. Ages included children, adults up to 60.
What other types of studies in this area are being conducted at Winship?
We are studying the role of different constituents in the graft (BM and PBSC) to determine which are most important in shaping transplant outcomes (relapse, GvHD). We have an active pre-clinical research program utilizing mouse models to address specific questions related to engraftment cell homing and specific pathways related to immune activation. In addition, we will participate in a clinical trial of a new way of mobilizing blood stems that avoids the need for five days of G-CSF and uses a CXCR4 antagonist called plerixafor to mobilize PBSC. The properties of the plerixafor-mobilized PBSC may be more similar to BM cells with respect to GvHD.
The Winship Cancer Institute of Emory University offers a collaborative approach for dealing with cancer that begins as soon as a patient is diagnosed. The program considers the emotional, psychological and physical symptoms associated with cancer and its treatment.
Winship Cancer Institute of Emory University
And options for patients may include cognitive therapy, antidepressants, or both. Anger, fear, and anxiety mixed with the physical and emotional side effects of cancer treatments can lead to depression during and even after treatment, when patients may feel isolated.
Darren Johnson spent his 19th birthday undergoing a bone marrow transplant. A few weeks earlier, Johnson had been diagnosed with myelodysplasia, a form of leukemia in which the bone marrow fails to produce enough normal blood cells. He endured a year of treatment and then a lengthy recovery. (Watch “When Life Goes On,” a short video about his story.)
Only relatively recently have health care providers turned serious attention to the emotional well-being of cancer patients. They have realized that easing the emotional burden of a cancer diagnosis for patients and families may actually improve treatment and outcome.
Encouraged by Emory’s success, Edmund Waller, MD, PhD, director of Emoryâ€™s Bone Marrow and Stem Cell Transplant Center says, “While 3,000 is a nice round number, it’s the middle of a growing and successful program. After 3,000 procedures, I know we all look forward to the future of this program.â€