Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation
Ailing Liu,
Shirong Li,
Vera Donnenberg,
Jing Fu,
Susanne M. Gollin,
Huihui Ma,
Caisheng Lu,
Donna B. Stolz,
Markus Y. Mapara,
Sara A. Monaghan,
Suzanne Lentzsch
Affiliations
Ailing Liu
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA
Shirong Li
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Division of Hematology/Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Vera Donnenberg
Department of Surgery and Pharmaceutical Sciences, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA
Jing Fu
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Division of Hematology/Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Susanne M. Gollin
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health and Cancer Institute, and the University of Pittsburgh Cell Culture and Cytogenetics Facility, PA, USA
Huihui Ma
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Caisheng Lu
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Donna B. Stolz
Department of Cell Biology and Physiology, University of Pittsburgh, PA, USA
Markus Y. Mapara
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Division of Hematology/Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Sara A. Monaghan
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Suzanne Lentzsch
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA, USA;Division of Hematology/Oncology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.