ArticleHaematologica2018
Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation.
Article in Haematologica, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader.Nature communications · 2026Article
- GSPT1-specific protein degradation is effective in preclinical models of chemoresistant MYCN-amplified neuroblastoma.Journal of experimental & clinical cancer research : CR · 2026Article
- Lenalidomide and pomalidomide modulate hematopoietic cell expansion and differentiation in the presence of MSC.International journal of hematology · 2024Article
- Using Bioinformatics and Machine Learning to Predict the Genetic Characteristics of Ferroptosis-Cuproptosis-Related Genes Associated with Sleep Deprivation.Nature and science of sleep · 2024Article
- Role of microRNAs and their downstream target transcription factors in zebrafish thrombopoiesis.Scientific reports · 2023Article
- Role of MicroRNAs and their Downstream Target Transcription Factors in Zebrafish Thrombopoiesis.Research square · 2023Article
- Expansion of Human Megakaryocyte-Lineage Progeny via Aryl Hydrocarbon Receptor Antagonism with CH223191.Stem cell reviews and reports · 2022Article
- CRL4Cancers · 2022Review
- Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy.Journal of personalized medicine · 2021Review
- Helios represses megakaryocyte priming in hematopoietic stem and progenitor cells.The Journal of experimental medicine · 2021Article
- Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications.International journal of molecular sciences · 2021Review
- Multifaceted Role of PRDM Proteins in Human Cancer.International journal of molecular sciences · 2020Review
- Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.