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

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3 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1688-1697
Number of pages10
JournalHaematologica
Volume103
Issue number10
DOIs
StatePublished - Sep 30 2018

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ASJC Scopus subject areas

  • Hematology

Cite this

Liu, A., Li, S., Donnenberg, V., Fu, J., Gollin, S. M., Ma, H., Lu, C., Stolz, D. B., Mapara, M. Y., Monaghan, S. A., & Lentzsch, S. (2018). Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation. Haematologica, 103(10), 1688-1697. https://doi.org/10.3324/haematol.2018.188227