Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation.
Immunomodulatory drugs downregulate IKZF1 leading to expansion of hematopoietic progenitors with concomitant block of megakaryocytic maturation.
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DOI：
10.3324/haematol.2018.188227
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发表时间：
2018-10
期刊：
影响因子：
10.1
通讯作者：
Lentzsch S
中科院分区：
文献类型：
--
作者：
Liu A;Li S;Donnenberg V;Fu J;Gollin SM;Ma H;Lu C;Stolz DB;Mapara MY;Monaghan SA;Lentzsch S
免疫调节药物来那度胺和泊马度胺在多发性骨髓瘤患者中产生高应答率，但与高血小板减少率和继发性血液系统恶性肿瘤的风险增加有关。在这里，我们证明了免疫调节药物通过下调IKZF1抑制早期巨核细胞的凋亡和促进早期巨核细胞的增殖，从而诱导造血祖细胞的自我更新和上调巨核细胞集落。在这个过程中，免疫调节药物降解IKZF1，随后下调其结合伙伴GATA1。这导致GATA1靶标减少，如ZFPM1和NFE2，导致巨核祖细胞扩张，同时抑制巨核细胞的成熟。GATA1的下调进一步降低了CCND1的表达，增加了CDKN2A的表达。GATA1的过表达消除了免疫调节药物的作用，恢复了巨核祖细胞的成熟。我们的数据不仅提供了免疫调节药物导致血小板减少的机制，而且有助于解释由于细胞周期增强和随后的干细胞库耗尽而导致的继发性恶性肿瘤和长期细胞减少的更高风险。
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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影响因子：
20.3
作者：
Koh, KR;Janz, M;Lentzsch, S
通讯作者：
Lentzsch, S
影响因子：
20.3
作者：
Lecine, P;Villeval, JL;Shivdasani, RA
通讯作者：
Shivdasani, RA
影响因子：
78.5
作者：
Bartlett, JB;Dredge, K;Dalgleish, AG
通讯作者：
Dalgleish, AG
影响因子：
6.2
作者：
Fouquet, Guillemette;Tardy, Stephanie;Leleu, Xavier
通讯作者：
Leleu, Xavier
影响因子：
20.3
作者：
Dijon, Marilyne;Bardin, Florence;Tonnelle, Cecile
通讯作者：
Tonnelle, Cecile