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

doi:10.1016/j.isci.2021.102651

Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia

iScience. 2021 May 25;24(6):102651. doi: 10.1016/j.isci.2021.102651. eCollection 2021 Jun 25.

Authors

Barry M Zee^{1

2}, Kamrine E Poels^{3

4}, Cong-Hui Yao⁵, Kimihito C Kawabata⁶, Gongwei Wu⁷, Cihangir Duy^{8

9}, William D Jacobus¹, Elizabeth Senior¹, Jennifer E Endress⁵, Ashwini Jambhekar^{1

10

11}, Scott B Lovitch¹², Jiexian Ma¹, Abhinav Dhall^{1

2}, Isaac S Harris⁵, M Andres Blanco¹, David B Sykes¹³, Jonathan D Licht¹⁴, David M Weinstock^{7

15}, Ari Melnick⁶, Marcia C Haigis⁵, Franziska Michor^{3

4

11

16

17

18}, Yang Shi^{1

2}

Affiliations

¹ Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
² Ludwig Institute for Cancer Research, Oxford University, OX3 7DQ, UK.
³ Department of Data Science, Dana Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁵ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁶ Division of Hematology-Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁸ Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
⁹ Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
¹⁰ Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
¹¹ The Ludwig Center at Harvard, Boston, MA 02115, USA.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁴ Division of Hematology and Oncology, University of Florida Health Care Center, Gainesville, FL 32610, USA.
¹⁵ Cancer Biology Program, Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
¹⁶ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
¹⁷ The Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
¹⁸ The Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

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.

Keywords: molecular biology; stem cell research; systems biology.

Abstract

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