Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia
Barry M. Zee,
Kamrine E. Poels,
Cong-Hui Yao,
Kimihito C. Kawabata,
Gongwei Wu,
Cihangir Duy,
William D. Jacobus,
Elizabeth Senior,
Jennifer E. Endress,
Ashwini Jambhekar,
Scott B. Lovitch,
Jiexian Ma,
Abhinav Dhall,
Isaac S. Harris,
M. Andres Blanco,
David B. Sykes,
Jonathan D. Licht,
David M. Weinstock,
Ari Melnick,
Marcia C. Haigis,
Franziska Michor,
Yang Shi
Affiliations
Barry M. Zee
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Ludwig Institute for Cancer Research, Oxford University, OX3 7DQ, UK
Kamrine E. Poels
Department of Data Science, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Cong-Hui Yao
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Kimihito C. Kawabata
Division of Hematology-Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
Gongwei Wu
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Cihangir Duy
Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
William D. Jacobus
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA
Elizabeth Senior
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA
Jennifer E. Endress
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Ashwini Jambhekar
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; The Ludwig Center at Harvard, Boston, MA 02115, USA
Scott B. Lovitch
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
Jiexian Ma
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA
Abhinav Dhall
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Ludwig Institute for Cancer Research, Oxford University, OX3 7DQ, UK
Isaac S. Harris
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
M. Andres Blanco
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA
David B. Sykes
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Jonathan D. Licht
Division of Hematology and Oncology, University of Florida Health Care Center, Gainesville, FL 32610, USA
David M. Weinstock
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Biology Program, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA
Ari Melnick
Division of Hematology-Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
Marcia C. Haigis
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Franziska Michor
Department of Data Science, Dana Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; The Ludwig Center at Harvard, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; The Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Yang Shi
Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Ludwig Institute for Cancer Research, Oxford University, OX3 7DQ, UK; Corresponding author
Summary: A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.
