Photo courtesy of St. Jude
Children’s Research Hospital
Research published in Cancer Cell appears to explain how the abnormal breakage and rearrangement of chromosomes in white blood cells triggers Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL).
Genomic analysis revealed 4 chromosomal rearrangements that all resulted in a truncated version of the erythropoietin receptor (EPOR) gene and drove white blood cells to proliferate out of control.
“To our knowledge, this is a previously unknown mechanism for leukemia,” said study author Charles Mullighan, MBBS, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Our search of cancer genomic data has shown that there are many other examples of chromosomal rearrangements that alter genes’ structure, but this type—where a truncating rearrangement leads to activation—is new.”
Although Dr Mullighan and his colleagues had previously identified an abnormal chromosome rearrangement in Ph-like ALL, little was known about the biological effects of that rearrangement. So they set out to pinpoint those effects by studying human leukemic cells and mouse cells engineered to mimic Ph-like ALL.
The investigators discovered the 4 rearrangements of EPOR, all of which resulted in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia. The proximal tyrosine essential for receptor activation was preserved, but distal regulatory residues were lost.
The team said these rearrangements resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation.
The investigators noted that the rearrangements were present in all of the leukemic cells from patients, which suggests these changes were fundamental to Ph-like ALL development. The team also showed that introducing truncated EPOR in mouse B-cell progenitors gave rise to ALL in mice.
Further investigation revealed that EPOR rearrangements arise early in the development of Ph-like ALL and persist as the disease progresses.
“That finding was important because it suggests that treatments for this leukemia targeting this receptor won’t just impact a subset of the leukemia cells, allowing others to keep proliferating,” said study author Ilaria Iacobucci, PhD, of St. Jude Children’s Research Hospital.
The investigators then found that human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition via treatment with ruxolitinib.
The team also cited the case of an adult patient treated at MD Anderson Cancer Research Center in Houston, Texas, whose genetic analysis revealed EPOR-rearranged ALL. That patient had not responded significantly to other chemotherapy drugs. But, when given ruxolitinib, the patient showed a major drop in leukemia cells.
In experiments with leukemic cells, the investigators found that ruxolitinib worked synergistically with 3 chemotherapeutic agents—dexamethasone, vincristine, and daunorubicin.
“We think these findings provide a useful road map for planning more accurate testing of combination chemotherapies,” Dr Mullighan said.
“These findings expand the number of ALL patients who should be amenable to precision medicine therapies that add targeted inhibitors to chemotherapy for ALL patents with specific genetic changes in the leukemia cells,” added study author Stephen Hunger, MD, of Children’s Hospital of Philadelphia in Pennsylvania.
Dr Hunger said the Children’s Oncology Group has developed a clinical trial testing this strategy with ruxolitinib, which will begin treating patients in mid-2016. Based on the results of the Cancer Cell research, the trial will include children with ALL and EPOR rearrangements.
