USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism

Johanna Melo-Cardenas; Yuanming Xu; Juncheng Wei; Can Tan; Sinyi Kong; Beixue Gao; Elena Montauti; Gina Kirsammer; Jonathan D. Licht; Jindan Yu; Peng Ji; John D. Crispino; Deyu Fang

doi:10.1182/blood-2017-10-811760

USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism

Johanna Melo-Cardenas, Yuanming Xu, Juncheng Wei, Can Tan, Sinyi Kong, Beixue Gao, Elena Montauti, Gina Kirsammer, Jonathan D. Licht, Jindan Yu, Peng Ji, John D. Crispino, Deyu Fang^*

^*Corresponding author for this work

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

54 Scopus citations

Abstract

Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic Kras^G12D/+. USP22 deficiency in Kras^G12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient Kras^G12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient Kras^G12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient Kras^G12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.

Original language	English (US)
Pages (from-to)	423-434
Number of pages	12
Journal	Blood
Volume	132
Issue number	4
DOIs	https://doi.org/10.1182/blood-2017-10-811760
State	Published - Jul 26 2018

Funding

The authors thank the Northwestern University Flow Cytometry Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553 and National Institutes of Health, Office of the Director Grant 1S10OD011996-01; the Northwestern University Pathology Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553; the Northwestern University NUSeq Core; and Matt Schipma for critical discussions and bioinformatics analyses. D.F. is supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants R01 AI079056, R01 AI108634, and National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR006634. J.M.-C. is supported by National Institutes of Health, National Heart, Lung, and Blood Institute Research Service Award Fellowship F31 HL136107-01.

ASJC Scopus subject areas

Hematology
Biochemistry
Cell Biology
Immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1182/blood-2017-10-811760

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@article{eab03f3a7cea4b5dbb9986af4a1efbc7,

title = "USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism",

abstract = "Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10\% and 50\% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+. USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient KrasG12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient KrasG12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient KrasG12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.",

author = "Johanna Melo-Cardenas and Yuanming Xu and Juncheng Wei and Can Tan and Sinyi Kong and Beixue Gao and Elena Montauti and Gina Kirsammer and Licht, \{Jonathan D.\} and Jindan Yu and Peng Ji and Crispino, \{John D.\} and Deyu Fang",

note = "Funding Information: The authors thank the Northwestern University Flow Cytometry Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553 and National Institutes of Health, Office of the Director Grant 1S10OD011996-01; the Northwestern University Pathology Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553; the Northwestern University NUSeq Core; and Matt Schipma for critical discussions and bioinformatics analyses. Funding Information: D.F. is supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants R01 AI079056, R01 AI108634, and National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR006634. J.M.-C. is supported by National Institutes of Health, National Heart, Lung, and Blood Institute Research Service Award Fellowship F31 HL136107-01. Publisher Copyright: {\textcopyright} 2018 by The American Society of Hematology.",

year = "2018",

month = jul,

day = "26",

doi = "10.1182/blood-2017-10-811760",

language = "English (US)",

volume = "132",

pages = "423--434",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "4",

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T1 - USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism

AU - Melo-Cardenas, Johanna

AU - Xu, Yuanming

AU - Wei, Juncheng

AU - Tan, Can

AU - Kong, Sinyi

AU - Gao, Beixue

AU - Montauti, Elena

AU - Kirsammer, Gina

AU - Licht, Jonathan D.

AU - Yu, Jindan

AU - Ji, Peng

AU - Crispino, John D.

AU - Fang, Deyu

N1 - Funding Information: The authors thank the Northwestern University Flow Cytometry Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553 and National Institutes of Health, Office of the Director Grant 1S10OD011996-01; the Northwestern University Pathology Core Facility, which is supported by National Institutes of Health, National Cancer Institute Grant P30 CA060553; the Northwestern University NUSeq Core; and Matt Schipma for critical discussions and bioinformatics analyses. Funding Information: D.F. is supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grants R01 AI079056, R01 AI108634, and National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR006634. J.M.-C. is supported by National Institutes of Health, National Heart, Lung, and Blood Institute Research Service Award Fellowship F31 HL136107-01. Publisher Copyright: © 2018 by The American Society of Hematology.

PY - 2018/7/26

Y1 - 2018/7/26

N2 - Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+. USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient KrasG12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient KrasG12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient KrasG12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.

AB - Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+. USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient KrasG12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient KrasG12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient KrasG12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.

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DO - 10.1182/blood-2017-10-811760

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AN - SCOPUS:85051766237

SN - 0006-4971

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JO - Blood

JF - Blood

IS - 4

ER -

USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism

Abstract

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ASJC Scopus subject areas

UN SDGs

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