RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia

Qi Han, Jinlong Ma, Yan Gu, Huihui Song, Malika Kapadia, Yuka Imamura, Sinisa Dovat, Chunhua Song, Zheng Ge

Research output: Contribution to journalArticle

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Abstract

The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.

Original languageEnglish (US)
Pages (from-to)3842-3850
Number of pages9
JournalJournal of Cancer
Volume10
Issue number16
DOIs
StatePublished - Jan 1 2019

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Genetic Recombination
Clonal Evolution
Carcinogenesis
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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title = "RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia",
abstract = "The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.",
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RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia. / Han, Qi; Ma, Jinlong; Gu, Yan; Song, Huihui; Kapadia, Malika; Imamura, Yuka; Dovat, Sinisa; Song, Chunhua; Ge, Zheng.

In: Journal of Cancer, Vol. 10, No. 16, 01.01.2019, p. 3842-3850.

Research output: Contribution to journalArticle

TY - JOUR

T1 - RAG1 high expression associated with IKZF1 dysfunction in adult B-cell acute lymphoblastic leukemia

AU - Han, Qi

AU - Ma, Jinlong

AU - Gu, Yan

AU - Song, Huihui

AU - Kapadia, Malika

AU - Imamura, Yuka

AU - Dovat, Sinisa

AU - Song, Chunhua

AU - Ge, Zheng

PY - 2019/1/1

Y1 - 2019/1/1

N2 - The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.

AB - The recombination mediated by recombination activating gene (RAG) is not only the dominant mutational process but also the predominant driver of oncogenic genomic rearrangement in acute lymphoblastic leukemia (ALL). It is further responsible for leukemic clonal evolution. In this study, significant RAG1 increase is observed in the subsets of B-ALL patients, and high expression of RAG1 is observed to be correlated with high proliferation markers. IKZF1-encoded protein, IKAROS, directly binds to the RAG1 promoter and regulates RAG1 expression in leukemic cells. CK2 inhibitor by increasing IKAROS activity significantly suppresses RAG1 expression in ALL in an IKAROS-dependent manner. Patients with IKZF1 deletion have significantly higher expression of RAG1 compared to that without IKZF1 deletion. CK2 inhibitor treatment also results in an increase in IKZF1 binding to the RAG1 promoter and suppression of RAG1 expression in primary ALL cells. Taken together, these results demonstrate that RAG1 high expression is associated with high proliferation markers in B-ALL. Our data for the first time proved that RAG1 expression is directly suppressed by IKAROS. Our results also reveal drive oncogenesis of B-ALL is driven by high expression of RAG1 with IKAROS dysfunction together, which have significance in an integrated prognostic model for adult ALL.

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