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Plasma Cell Disorders
Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation
Ailing Liu,1* Shirong Li,1,2* Vera Donnenberg,3 Jing Fu,1,2 Susanne M. Gollin,4 Huihui Ma,1,5 Caisheng Lu,1,5 Donna B. Stolz,6 Markus Y. Mapara,1,2,5
Sara A. Monaghan7 and Suzanne Lentzsch1,2
1
ABSTRACT
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 pro- genitors 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 part- ner, 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 megakary- ocytic 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 cytope- nia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.
Introduction
Lenalidomide (LEN, CC-5013) and pomalidomide (POM, CC-4047) are immunomodulatory drugs (IMiDs), analogues of thalidomide, which have several cellular effects including immunomodulatory, anti-angiogenic, anti-inflammatory and anti-proliferative effects.1-3 In multiple myeloma (MM) cells, LEN binds to cere- blon and thereby, is able to target two specific B-cell transcription factors, Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) for proteasomal degrada- tion4,5 and subsequently affect transcription factors critical for multiple myeloma (MM) growth, such as CCAAT-enhancer-binding protein beta (C/EBPb)6 and IRF4.7 We have shown that IKZF1 is also expressed in CD34+ cells and undergoes degra- dation after ubiquitination of cereblon when cells are treated with IMiDs.8 LEN is considered a therapeutic breakthrough in the treatment of MM.9 POM is the newest IMiD, and appears to be more potent than LEN in MM.10 However, the use of IMiDs is associated with neutropenia, thrombocytopenia, bone marrow failure and stem cell mobilization.9,11,12 In addition, there is a concern of an increased risk
Haematologica 2018 Volume 103(10):1688-1697
Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, PA; 2Division of Hematology/Oncology, College of Physicians and Surgeons, Columbia University, New York, NY; 3Department of Surgery and Pharmaceutical Sciences, University of Pittsburgh School of Medicine and Cancer Institute, PA; 4Department 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; 5Columbia Center for Translational Immunology, College of Physicians and Surgeons, Columbia University, New York, NY; 6Department of Cell Biology and Physiology, University of Pittsburgh, PA; 7Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
*AL and SL contributed equally to this work
Correspondence:
sl3440@columbia.edu
Received: January 19, 2018. Accepted: June 25, 2018. Pre-published: June 28, 2018.
doi:10.3324/haematol.2018.188227
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/10/1688
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