Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.

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Publication Details

Journal
JCI Insight
Published
2026-02-23
DOI
https://doi.org/10.1172/jci.insight.193779
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
0.00

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article

Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia

Thomas M. Sesterhenn, Ben Wronowski, Nives Zimmermann, Erin K. Hertlein et al.
JCI Insight
Protein Tyrosine Phosphatases
article

Characterization of the clonal hierarchy and immunophenotype of PTPN11 mutations in acute myeloid leukemia

Thomas M. Sesterhenn, Ben Wronowski, Nives Zimmermann, Erin K. Hertlein, Casie Furby, Eunice S. Wang, Sydney Fobare, Shesh Nath Rai, Marissa Long, Kaytlynn Fyock, K. R. Quinn, Deedra Nicolet, Carolyn Cheney, John P Perentesis, Wen-Mei Yu, Jianmin Pan, James R. Lerma, Andrew Carroll, Kinsey Bryant, John C. Byrd, Bayard Powell, Robert L. Bowman, Richard Stone, Chia Sharpe, Chandrashekhar Pasare, Megan E. Johnstone, Ann-Kathrin Eisfeld, Cheng-Kui Qu, Krzysztof Mrózek
article en

Abstract

Mutations in protein tyrosine phosphatase non-receptor type 11 (PTPN11) have been considered late acquired mutations in acute myeloid leukemia (AML) development. Using single-cell DNA sequencing, we found that PTPN11 mutations can occur as initiating events in some patients with AML when accompanied by strong oncogenic drivers, commonly NPM1 mutations. The resulting AML has a diverse set of variably differentiated myeloid cells with few myeloid cells that lack leukemic mutations. The role of Ptpn11 as a codriver was confirmed in a murine model that exhibits an AML phenotype with a comparable immune diversity that is serially engraftable and reconstituted from early precursor cells. Furthermore, lineage-negative bone marrow cells from these mice reconstitute the full diversity of mature myeloid cells, and these cells exhibit an altered cytokine response after physiologic stimulation. Our work highlights how PTPN11-mutated AML is derived from a multitude of codominant and late acquired aberrations that have a previously unrecognized differentiated myeloid clonal expansion potentially contributing to pathogenesis of the disease.

JCI InsightVol. 11(4)
Atrium Health Wake Forest Baptist (US), Cincinnati Children's Hospital Medical Center (US), Roswell Park Comprehensive Cancer Center (US), Hofstra University (US), Emory University (US), University of Alabama at Birmingham (US), National Cancer Center (US), CancerCare (US), Alliance Data (United States) (US), Dana-Farber/Harvard Cancer Center (US), Wake Forest Baptist Comprehensive Cancer Center, The Ohio State University (US), University of Cincinnati (US), Bloomfield College (US), University of Pennsylvania (US), University of Cincinnati Medical Center (US)
U.S. Department of Defense, Ohio State University, Cincinnati Children's Hospital Medical Center, Pelotonia, National Institutes of Health, National Cancer Institute
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Protein Tyrosine Phosphatases
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