Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors

Theodore P. Braun; Joseph Estabrook; Zachary Schonrock; Brittany M. Curtiss; Lucie Darmusey; Jommel Macaraeg; Trevor Enright; Cody Coblentz; Rowan Callahan; William Yashar; Akram Taherinasab; Hisham Mohammed; Daniel J. Coleman; Brian J. Druker; Emek Demir; Theresa A. Lusardi; Julia E. Maxson

doi:10.1038/s41375-022-01792-x

Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors

Theodore P. Braun, Joseph Estabrook, Zachary Schonrock, Brittany M. Curtiss, Lucie Darmusey, Jommel Macaraeg, Trevor Enright, Cody Coblentz, Rowan Callahan, William Yashar, Akram Taherinasab, Hisham Mohammed, Daniel J. Coleman, Brian J. Druker, Emek Demir, Theresa A. Lusardi, Julia E. Maxson

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

Abstract

Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.

Original language	English (US)
Pages (from-to)	478-487
Number of pages	10
Journal	Leukemia
Volume	37
Issue number	2
DOIs	https://doi.org/10.1038/s41375-022-01792-x
State	Published - Feb 2023

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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Braun, T. P., Estabrook, J., Schonrock, Z., Curtiss, B. M., Darmusey, L., Macaraeg, J., Enright, T., Coblentz, C., Callahan, R., Yashar, W., Taherinasab, A., Mohammed, H., Coleman, D. J., Druker, B. J., Demir, E., Lusardi, T. A., & Maxson, J. E. (2023). Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors. Leukemia, 37(2), 478-487. https://doi.org/10.1038/s41375-022-01792-x

Braun, TP, Estabrook, J, Schonrock, Z, Curtiss, BM, Darmusey, L, Macaraeg, J, Enright, T, Coblentz, C, Callahan, R, Yashar, W, Taherinasab, A, Mohammed, H, Coleman, DJ, Druker, BJ , Demir, E, Lusardi, TA & Maxson, JE 2023, 'Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors', Leukemia, vol. 37, no. 2, pp. 478-487. https://doi.org/10.1038/s41375-022-01792-x

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title = "Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors",

abstract = "Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.",

author = "Braun, {Theodore P.} and Joseph Estabrook and Zachary Schonrock and Curtiss, {Brittany M.} and Lucie Darmusey and Jommel Macaraeg and Trevor Enright and Cody Coblentz and Rowan Callahan and William Yashar and Akram Taherinasab and Hisham Mohammed and Coleman, {Daniel J.} and Druker, {Brian J.} and Emek Demir and Lusardi, {Theresa A.} and Maxson, {Julia E.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

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doi = "10.1038/s41375-022-01792-x",

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AU - Braun, Theodore P.

AU - Estabrook, Joseph

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AU - Curtiss, Brittany M.

AU - Darmusey, Lucie

AU - Macaraeg, Jommel

AU - Enright, Trevor

AU - Coblentz, Cody

AU - Callahan, Rowan

AU - Yashar, William

AU - Taherinasab, Akram

AU - Mohammed, Hisham

AU - Coleman, Daniel J.

AU - Druker, Brian J.

AU - Demir, Emek

AU - Lusardi, Theresa A.

AU - Maxson, Julia E.

PY - 2023/2

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N2 - Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.

AB - Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.

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Asxl1 deletion disrupts MYC and RNA polymerase II function in granulocyte progenitors

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