Journal
ISCIENCE
Volume 24, Issue 5, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.isci.2021.102410
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Funding
- National Key Research and Development Program of China [2018YFA0107802]
- National Natural Science Foundation of China [81770143, 81970130]
- Shanghai Commission of Science and Technology [17PJ1405800]
- Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant [20171902]
- Shanghai Pujiang Program [17PJ1405800]
- Shanghai DF Scholarship
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ATRA can induce near-normal differentiation towards mature granulocytes in APL/AML-M3 cells, but induces incomplete and promiscuous differentiation in AML-M2 cells, characterized by coinduction of myelopoiesis and lymphopoiesis gene expression programs.
All-trans retinoid acid (ATRA) can induce terminal differentiation of acute promyelocytic leukemia (APL), also known as the M3 subtype of acute myeloid leukemia (AML). However, non-APL types of AML respond poorly to ATRA-induced differentiation, and the mechanism underlying cell-type-specific resistance against ATRA remains unclear. Here, we use single-cell transcriptome analysis to compare the differentiation trajectories of two AML cell types during ATRA treatment. We show that in NB4 (APL/AML-M3) cells, ATRA activates canonical myeloid lineage factors-including SPI1, CEBPE, and STAT1-to direct near-normal differentiation toward mature granulocytes. By contrast, in HL60 (AML-M2) cells, ATRA-induced differentiation is incomplete and promiscuous, which is characterized by coinduction of both myelopoiesis and lymphopoiesis gene expression programs, as well as transient activation of cis-regulatory elements associated with myeloid differentiation. Our study suggests that the differentiation inducing capacity of ATRA in certain subtypes of AML may be compromised by therapy-induced lineage promiscuity.
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