Molecular map reveals insights into the genetic drivers of chronic lymphocytic leukemia
New map of chronic lymphocytic leukemia could potentially help identify new diagnostic markers, offer more accurate prognoses, and develop novel treatments.
By Tracy Hampton
Credit: National Institutes of Allergy and Infectious Diseases, National Institutes of Health
Colorized scanning electron micrograph of a B cell lymphocyte from a human donor.
A newly constructed map of the landscape of genetic changes in chronic lymphocytic leukemia (CLL), a type of cancer of the blood and bone marrow that exists in diverse forms and arises from various causes, provides a better understanding of this complex malignancy that could lead to more accurate prognoses for patients, improved diagnostics, and novel treatments. The work is published in Nature Genetics and was conducted by an international collaboration of investigators, including teams from the Broad Institute of MIT and Harvard, the Mass General Cancer Center, and the Dana-Farber Cancer Institute.
CLL exists as either a slowly or rapidly growing cancer and has been linked with certain genetic mutations, but it has yet to be fully characterized. Previous analyses have provided only fragments of a CLL "map," each focusing on particular types of patients or limited data. To provide a more thorough understanding of the biological underpinnings of CLL and its molecular subtypes, scientists set out to construct a map from the largest CLL dataset to date.
To build the CLL map, the team analyzed variations in genetic sequences, gene expression patterns, and chemical modifications to DNA — or genomic, transcriptomic, and epigenomic data — from 1,148 patients.
"Such a CLL map could eventually be leveraged in the clinic, wherein the genomic features of new patients can be compared with the treatments and outcomes of patients with similar genetic profiles," says institute member and co-senior author Catherine Wu, also chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School. "This profiling could potentially help more accurately tailor prognosis and treatment of a new patient based on their particular molecular features, getting closer to precision medicine."
The scientists identified 202 genes (109 of which were novel) that when mutated could potentially drive CLL, and they refined the characterization of subtypes of CLL with distinct genomic characteristics and prognoses. Beyond genetic sequences, the expression patterns of certain genes further subcategorized CLL and provided valuable prognostic information.
"Our study has revealed that the genetic and biologic landscape of CLL is more complex than previously appreciated," says institute member and co-senior author Gad Getz, director of the Cancer Genome Computational Analysis group at Broad and director of Bioinformatics at the Mass General Cancer Center.
Patients’ clinical outcomes were associated with a combination of genomic, transcriptomic, and epigenomic features — so that integrating these data could predict a patient’s likelihood of experiencing remission versus developing more advanced cancer.
"We are releasing a CLL map ‘portal’ that is based on the CLL map and will be an interactive website for translational researchers to use as a resource for further investigation — such as learning more about the different drivers and subtypes of CLL," says Getz.
The study was also led by José I. Martín-Subero (IDIBAPS), Xose S. Puente (Universidad de Oviedo), and Elias Campo (IDIBAPS and Hospital Clinic of Barcelona) from Spain; and Stephan Stilgenbauer (Ulm University) from Germany.
Additional study authors include the co–first authors Binyamin A. Knisbacher, Ziao Lin, Cynthia K. Hahn, Ferran Nadeu, and Martí Duran-Ferrer, alongside many additional co-authors: Kristen E. Stevenson, Eugen Tausch, Julio Delgado, Alex Barbera-Mourelle, Amaro Taylor-Weiner, Pablo Bousquets-Muñoz, Ander Diaz-Navarro, Andrew Dunford, Shankara Anand, Helene Kretzmer, Jesus Gutierrez-Abril, Sara López-Tamargo, Stacey M. Fernandes, Clare Sun, Mariela Sivina, Laura Z. Rassenti, Christof Schneider, Shuqiang Li, Laxmi Parida, Alexander Meissner, François Aguet, Jan A. Burger, Adrian Wiestner, Thomas J. Kipps, Jennifer R. Brown, Michael Hallek, Chip Stewart, and Donna S. Neuberg.
This work was supported by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project.
Adapted from a press release from Massachusetts General Hospital.