Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia

Rekha Pal, Sara A. Monaghan, Andrea Cortese Hassett, Markus Y. Mapara, Peter Schafer, G. David Roodman, Margaret V. Ragni, Lynn Moscinski, Alan List, Suzanne Lentzsch

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.

Original languageEnglish (US)
Pages (from-to)605-614
Number of pages10
JournalBlood
Volume115
Issue number3
DOIs
StatePublished - Jan 21 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Pal, R., Monaghan, S. A., Hassett, A. C., Mapara, M. Y., Schafer, P., Roodman, G. D., Ragni, M. V., Moscinski, L., List, A., & Lentzsch, S. (2010). Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia. Blood, 115(3), 605-614. https://doi.org/10.1182/blood-2009-05-221077