Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution

Qingfei Jiang; Jane Isquith; Luisa Ladel; Adam Mark; Frida Holm; Cayla Mason; Yudou He; Phoebe Mondala; Isabelle Oliver; Jessica Pham; Wenxue Ma; Eduardo Reynoso; Shawn Ali; Isabella Jamieson Morris; Raymond Diep; Chanond Nasamran; Guorong Xu; Roman Sasik; Sara Brin Rosenthal; Amanda Birmingham; Sanja Coso; Gabriel Pineda; Leslie Crews; Mary E. Donohoe; J. Craig Venter; Thomas Whisenant; Ruben A. Mesa; Ludmil B. Alexandrov; Kathleen M. Fisch; Catriona Jamieson

doi:10.1016/j.celrep.2020.108670

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution

Qingfei Jiang, Jane Isquith, Luisa Ladel, Adam Mark, Frida Holm, Cayla Mason, Yudou He, Phoebe Mondala, Isabelle Oliver, Jessica Pham, Wenxue Ma, Eduardo Reynoso, Shawn Ali, Isabella Jamieson Morris, Raymond Diep, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda BirminghamSanja Coso, Gabriel Pineda, Leslie Crews, Mary E. Donohoe, J. Craig Venter, Thomas Whisenant, Ruben A. Mesa, Ludmil B. Alexandrov, Kathleen M. Fisch, Catriona Jamieson

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	108670
Journal	Cell Reports
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2020.108670
State	Published - Jan 26 2021
Externally published	Yes

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Biochemistry, Genetics and Molecular Biology(all)

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Jiang, Q., Isquith, J., Ladel, L., Mark, A., Holm, F., Mason, C., He, Y., Mondala, P., Oliver, I., Pham, J., Ma, W., Reynoso, E., Ali, S., Morris, I. J., Diep, R., Nasamran, C., Xu, G., Sasik, R., Rosenthal, S. B., ... Jamieson, C. (2021). Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution. Cell Reports, 34(4), [108670]. https://doi.org/10.1016/j.celrep.2020.108670

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution. / Jiang, Qingfei; Isquith, Jane; Ladel, Luisa; Mark, Adam; Holm, Frida; Mason, Cayla; He, Yudou; Mondala, Phoebe; Oliver, Isabelle; Pham, Jessica; Ma, Wenxue; Reynoso, Eduardo; Ali, Shawn; Morris, Isabella Jamieson; Diep, Raymond; Nasamran, Chanond; Xu, Guorong; Sasik, Roman; Rosenthal, Sara Brin; Birmingham, Amanda; Coso, Sanja; Pineda, Gabriel; Crews, Leslie; Donohoe, Mary E.; Venter, J. Craig; Whisenant, Thomas; Mesa, Ruben A.; Alexandrov, Ludmil B.; Fisch, Kathleen M.; Jamieson, Catriona.

In: Cell Reports, Vol. 34, No. 4, 108670, 26.01.2021.

Research output: Contribution to journal › Article › peer-review

Jiang, Q, Isquith, J, Ladel, L, Mark, A, Holm, F, Mason, C, He, Y, Mondala, P, Oliver, I, Pham, J, Ma, W, Reynoso, E, Ali, S, Morris, IJ, Diep, R, Nasamran, C, Xu, G, Sasik, R, Rosenthal, SB, Birmingham, A, Coso, S, Pineda, G, Crews, L, Donohoe, ME, Venter, JC, Whisenant, T, Mesa, RA, Alexandrov, LB, Fisch, KM & Jamieson, C 2021, 'Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution', Cell Reports, vol. 34, no. 4, 108670. https://doi.org/10.1016/j.celrep.2020.108670

Jiang, Qingfei ; Isquith, Jane ; Ladel, Luisa ; Mark, Adam ; Holm, Frida ; Mason, Cayla ; He, Yudou ; Mondala, Phoebe ; Oliver, Isabelle ; Pham, Jessica ; Ma, Wenxue ; Reynoso, Eduardo ; Ali, Shawn ; Morris, Isabella Jamieson ; Diep, Raymond ; Nasamran, Chanond ; Xu, Guorong ; Sasik, Roman ; Rosenthal, Sara Brin ; Birmingham, Amanda ; Coso, Sanja ; Pineda, Gabriel ; Crews, Leslie ; Donohoe, Mary E. ; Venter, J. Craig ; Whisenant, Thomas ; Mesa, Ruben A. ; Alexandrov, Ludmil B. ; Fisch, Kathleen M. ; Jamieson, Catriona. / Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution. In: Cell Reports. 2021 ; Vol. 34, No. 4.

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title = "Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution",

abstract = "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.",

keywords = "Enter keywords here",

author = "Qingfei Jiang and Jane Isquith and Luisa Ladel and Adam Mark and Frida Holm and Cayla Mason and Yudou He and Phoebe Mondala and Isabelle Oliver and Jessica Pham and Wenxue Ma and Eduardo Reynoso and Shawn Ali and Morris, {Isabella Jamieson} and Raymond Diep and Chanond Nasamran and Guorong Xu and Roman Sasik and Rosenthal, {Sara Brin} and Amanda Birmingham and Sanja Coso and Gabriel Pineda and Leslie Crews and Donohoe, {Mary E.} and Venter, {J. Craig} and Thomas Whisenant and Mesa, {Ruben A.} and Alexandrov, {Ludmil B.} and Fisch, {Kathleen M.} and Catriona Jamieson",

note = "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: {\textcopyright} 2020 The Author(s)",

year = "2021",

month = jan,

day = "26",

doi = "10.1016/j.celrep.2020.108670",

language = "English (US)",

volume = "34",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

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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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Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution

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