Chromosomal Rearrangements Initiate High-risk Leukemia
Abnormal breakage and chromosomal rearrangement in white blood cells result in a particularly aggressive, Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL), according to a new study. Chromosomal rearrangements are a characteristic of ALL.1
In this study, published in Cancer Cell, researchers discovered 4 distinct chromosomal rearrangements that all result in heightened erythropoietin stimulation and increased JAK-STAT activation. Researchers used both human and mouse leukemic cells to examine these rearrangements.
All 4 rearrangements were truncating rearrangements that resulted in receptor activation, loss of distal regulatory residues, and a leukemic state.
"To our knowledge, this is a previously unknown mechanism for leukemia," said Charles Mullighan, MBBS, MD, a member of the Department of Pathology at St. Jude Children's Research Hospital, in Memphis, Tennessee, and lead author of the study.
"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."
This study revealed chromosomal rearrangements occur early in the development of leukemia and persist as the cancer progresses. This early development of cancer in the cell lines suggested that treatment would affect all leukemic cells rather than just a subset of the cancerous cells.
The study also identified potential therapeutic approaches. Ruxolitinib administration to both the human and mouse leukemic cells inhibited the heightened erythropoietin stimulation and increased JAK-STAT activation.
In addition, ruxolitinib administration enhanced the effectiveness of dexamethasone, vincristine, and daunorubicin, 3 widely used chemotherapy drugs. Ruxolitinib, which inhibits JAK signaling, is currently FDA approved for polycythemia vera, a chronic bone marrow disease, and for myelofibrosis, a chronic blood cancer.
"We think these findings provide a useful road map for planning more accurate testing of combination chemotherapies," Mullighan said.
Clinical trials with ruxolitinib that will address this testing strategy and include children with these rearrangements are planned to begin mid-2016.
This research was supported by grants from the National Cancer Institute, the St. Baldrick's Foundation, the Leukemia and Lymphoma Society, the Lady Tata Memorial Trust, Alex's Lemonade Stand Foundation, ALSAC, and Stand Up to Cancer.
1. Iacobucci I, Li Y, Roberts, KG, et al. Truncating erythropoietin receptor rearrangements in acute lymphoblastic leukemia. Cancer Cell. 2016;29(2):186-200.