Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition

Kathryn S. Potts; Rosannah C. Cameron; Amina Metidji; Noura Ghazale; La Shanale Wallace; Ana I. Leal-Cervantes; Reid Palumbo; Juan Martin Barajas; Varun Gupta; Srinivas Aluri; Kith Pradhan; Jacquelyn A. Myers; Mia McKinstry; Xiaoying Bai; Gaurav S. Choudhary; Aditi Shastri; Amit Verma; Esther A. Obeng; Teresa V. Bowman

doi:10.1016/j.celrep.2022.111825

Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition

Kathryn S. Potts, Rosannah C. Cameron, Amina Metidji, Noura Ghazale, La Shanale Wallace, Ana I. Leal-Cervantes, Reid Palumbo, Juan Martin Barajas, Varun Gupta, Srinivas Aluri, Kith Pradhan, Jacquelyn A. Myers, Mia McKinstry, Xiaoying Bai, Gaurav S. Choudhary, Aditi Shastri, Amit Verma, Esther A. Obeng, Teresa V. Bowman

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

2 Scopus citations

Abstract

Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies.

Original language	English (US)
Article number	111825
Journal	Cell Reports
Volume	41
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.111825
State	Published - Dec 13 2022

Keywords

CP: Molecular biology
CP: Stem cell research
SF3B1
STAT3
hematopoietic stem and progenitor cell
myelodysplastic syndrome
splicing factor
zebrafish

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.111825

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Potts, K. S., Cameron, R. C., Metidji, A., Ghazale, N., Wallace, L. S., Leal-Cervantes, A. I., Palumbo, R., Barajas, J. M., Gupta, V., Aluri, S., Pradhan, K., Myers, J. A., McKinstry, M., Bai, X., Choudhary, G. S., Shastri, A., Verma, A., Obeng, E. A., & Bowman, T. V. (2022). Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition. Cell Reports, 41(11), Article 111825. https://doi.org/10.1016/j.celrep.2022.111825

Potts, KS, Cameron, RC, Metidji, A, Ghazale, N, Wallace, LS, Leal-Cervantes, AI, Palumbo, R, Barajas, JM, Gupta, V , Aluri, S , Pradhan, K, Myers, JA, McKinstry, M, Bai, X, Choudhary, GS, Shastri, A , Verma, A, Obeng, EA & Bowman, TV 2022, 'Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition', Cell Reports, vol. 41, no. 11, 111825. https://doi.org/10.1016/j.celrep.2022.111825

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title = "Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition",

abstract = "Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies.",

keywords = "CP: Molecular biology, CP: Stem cell research, SF3B1, STAT3, hematopoietic stem and progenitor cell, myelodysplastic syndrome, splicing factor, zebrafish",

author = "Potts, {Kathryn S.} and Cameron, {Rosannah C.} and Amina Metidji and Noura Ghazale and Wallace, {La Shanale} and Leal-Cervantes, {Ana I.} and Reid Palumbo and Barajas, {Juan Martin} and Varun Gupta and Srinivas Aluri and Kith Pradhan and Myers, {Jacquelyn A.} and Mia McKinstry and Xiaoying Bai and Choudhary, {Gaurav S.} and Aditi Shastri and Amit Verma and Obeng, {Esther A.} and Bowman, {Teresa V.}",

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doi = "10.1016/j.celrep.2022.111825",

language = "English (US)",

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T1 - Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition

AU - Potts, Kathryn S.

AU - Cameron, Rosannah C.

AU - Metidji, Amina

AU - Ghazale, Noura

AU - Wallace, La Shanale

AU - Leal-Cervantes, Ana I.

AU - Palumbo, Reid

AU - Barajas, Juan Martin

AU - Gupta, Varun

AU - Aluri, Srinivas

AU - Pradhan, Kith

AU - Myers, Jacquelyn A.

AU - McKinstry, Mia

AU - Bai, Xiaoying

AU - Choudhary, Gaurav S.

AU - Shastri, Aditi

AU - Verma, Amit

AU - Obeng, Esther A.

AU - Bowman, Teresa V.

PY - 2022/12/13

Y1 - 2022/12/13

N2 - Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies.

AB - Hematopoietic stem and progenitor cells (HSPCs) sustain lifelong hematopoiesis. Mutations of pre-mRNA splicing machinery, especially splicing factor 3b, subunit 1 (SF3B1), are early lesions found in malignancies arising from HSPC dysfunction. However, why splicing factor deficits contribute to HSPC defects remains incompletely understood. Using zebrafish, we show that HSPC formation in sf3b1 homozygous mutants is dependent on STAT3 activation. Clinically, mutations in SF3B1 are heterozygous; thus, we explored if targeting STAT3 could be a vulnerability in these cells. We show that SF3B1 heterozygosity confers heightened sensitivity to STAT3 inhibition in zebrafish, mouse, and human HSPCs. Cells carrying mutations in other splicing factors or treated with splicing modulators are also more sensitive to STAT3 inhibition. Mechanistically, we illustrate that STAT3 inhibition exacerbates aberrant splicing in SF3B1 mutant cells. Our findings reveal a conserved vulnerability of splicing factor mutant HSPCs that could allow for their selective targeting in hematologic malignancies.

KW - CP: Molecular biology

KW - CP: Stem cell research

KW - SF3B1

KW - STAT3

KW - hematopoietic stem and progenitor cell

KW - myelodysplastic syndrome

KW - splicing factor

KW - zebrafish

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SN - 2211-1247

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JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 111825

ER -

Splicing factor deficits render hematopoietic stem and progenitor cells sensitive to STAT3 inhibition

Abstract

Keywords

ASJC Scopus subject areas

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