Immunomodulatory derivatives induce PU.1 down-regulation, myeloid maturation arrest, and neutropenia.
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.
Pal
Rekha
R
Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, PA, USA.
Monaghan
Sara A
SA
Hassett
Andrea Cortese
AC
Mapara
Markus Y
MY
Schafer
Peter
P
Roodman
G David
GD
Ragni
Margaret V
MV
Moscinski
Lynn
L
List
Alan
A
Lentzsch
Suzanne
S
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000077269:Lenalidomide; D008954:Models, Biological; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009503:Neutropenia / Q000139:chemically induced* / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D054556:Venous Thromboembolism / Q000209:etiology; D000099232:Proto-Oncogene Protein Spi-1
D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor; D007155:Immunologic Factors; D000077269:Lenalidomide; D011518:Proto-Oncogene Proteins; D013792:Thalidomide; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C467566:pomalidomide