TY - JOUR
T1 - Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution
AU - Jiang, Qingfei
AU - Isquith, Jane
AU - Ladel, Luisa
AU - Mark, Adam
AU - Holm, Frida
AU - Mason, Cayla
AU - He, Yudou
AU - Mondala, Phoebe
AU - Oliver, Isabelle
AU - Pham, Jessica
AU - Ma, Wenxue
AU - Reynoso, Eduardo
AU - Ali, Shawn
AU - Morris, Isabella Jamieson
AU - Diep, Raymond
AU - Nasamran, Chanond
AU - Xu, Guorong
AU - Sasik, Roman
AU - Rosenthal, Sara Brin
AU - Birmingham, Amanda
AU - Coso, Sanja
AU - Pineda, Gabriel
AU - Crews, Leslie
AU - Donohoe, Mary E.
AU - Venter, J. Craig
AU - Whisenant, Thomas
AU - Mesa, Ruben A.
AU - Alexandrov, Ludmil B.
AU - Fisch, Kathleen M.
AU - Jamieson, Catriona
N1 - Funding Information:
We would like to thank Human Longevity Inc. (HLI) for whole-genome sequencing analysis guidance. We would like to thank our funding agencies for their vital support, including NIH/NCI R01CA205944, NIH/NIDDK R01DK114468-01, NIH/NCI 2P30CA023100-28, CIRM TRAN1-10540, MPN Research Foundation, LLS Blood Cancer Discoveries, NASA NRA NNJ13ZBG001N, and NIH/NCATS UL1TR001442. Q.J. was supported by NIH/NCI K22 CA229606. F.H. was funded by the Swedish Childhood Cancer Foundation, Barncancerfonden. Also, we would like to thank the Koman Family Foundation, the Strauss Family Foundation, the Sanford Stem Cell Clinical Center, the UC San Diego Moores Cancer Center, and the Moores Family Foundation for their generous support. Q.J. J.I. F.H. L.C. C.M. P.M. I.J.M. S.A. W.M. R.D. J.P. E.R. G.P. M.E.D. L.L. and C.J. performed experiments, data analysis, and/or experimental planning. L.B.A. Y.H. A.M. G.X. T.W. C.N. R.S. A.B. S.B.R. and K.F. performed the computational genomics analyses, including transcriptome, RNA editing, pathway, and whole-genome analysis, supervised by K.M.F. Q.J. J.I. F.H. I.O. J.C.V. R.A.M. S.C. K.M.F. and C.J. wrote the manuscript, which was reviewed and edited by all authors. C.J. supervised all aspects of the project. The authors declare no competing interests.
Funding Information:
We would like to thank Human Longevity Inc. (HLI) for whole-genome sequencing analysis guidance. We would like to thank our funding agencies for their vital support, including NIH/NCI R01CA205944 , NIH/NIDDK R01DK114468-01 , NIH/NCI 2P30CA023100-28 , CIRM TRAN1-10540 , MPN Research Foundation , LLS Blood Cancer Discoveries , NASA NRA NNJ13ZBG001N , and NIH/NCATS UL1TR001442 . Q.J. was supported by NIH / NCI K22 CA229606 . F.H. was funded by the Swedish Childhood Cancer Foundation, Barncancerfonden . Also, we would like to thank the Koman Family Foundation , the Strauss Family Foundation , the Sanford Stem Cell Clinical Center , the UC San Diego Moores Cancer Center , and the Moores Family Foundation for their generous support.
Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1/26
Y1 - 2021/1/26
N2 - Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.
AB - Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.
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U2 - 10.1016/j.celrep.2020.108670
DO - 10.1016/j.celrep.2020.108670
M3 - Article
C2 - 33503434
AN - SCOPUS:85099851047
VL - 34
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
M1 - 108670
ER -