TY - JOUR
T1 - Clinical responsiveness to all-trans retinoic acid is potentiated by lsd1 inhibition and associated with a quiescent transcriptome in myeloid malignancies
AU - Tayari, Mina M.
AU - Dos Santos, Helena G.
AU - Kwon, Deukwoo
AU - Bradley, Terrence J.
AU - Thomassen, Amber
AU - Chen, Charles
AU - Dinh, Yvonne
AU - Perez, Aymee
AU - Zelent, Arthur
AU - Morey, Lluis
AU - Cimmino, Luisa
AU - Shiekhattar, Ramin
AU - Swords, Ronan T.
AU - Watts, Justin M.
N1 - Funding Information:
We gratefully acknowledge the help provided by Maria “Ken” Figueroa and Stephen D. Nimer for their constructive comments. We would like to thank Felipe Beckedorff for his assistance on the preliminary analysis of the patient samples, and his insightful advice. We thank our laboratory members and the Bioinformatics core at Sylvester Comprehensive Cancer Center for support and helpful discussions. We also thank the Oncogenomics core facility for performing the high-throughput sequencing. This work was supported by grants from The Leukemia & Lymphoma Society, Specialized Center of Research Program (to principal investigator, Stephen D. Nimer), Project 1 (to R. Shiekhattar, R.T. Morey, and J.M. Watts); NCI 5R21CA202488-02 (to principal investigator, R.T. Swords and J.M. Watts); NIH/NCI, The Sylvester Cancer Center Support Grant, 1P30CA240139-01 (to principal investigator, Stephen D. Nimer); and the Sylvester Comprehensive Cancer Center.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - Purpose: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Patients and Methods: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). Results: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. Conclusions: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
AB - Purpose: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS). Patients and Methods: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily). Results: ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid-target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response. Conclusions: These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
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U2 - 10.1158/1078-0432.CCR-20-4054
DO - 10.1158/1078-0432.CCR-20-4054
M3 - Article
C2 - 33495312
AN - SCOPUS:85104894043
SN - 1078-0432
VL - 27
SP - 1893
EP - 1903
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -