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Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice
Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important...
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Published in: | Blood advances 2017-11, Vol.1 (25), p.2361-2374 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | Despite recent advances in treatment, human precursor B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging clinical entity. Recent genome-wide studies have uncovered frequent genetic alterations involving RAS pathway mutations and loss of the INK4A/ARF locus, suggesting their important role in the pathogenesis, relapse, and chemotherapy resistance of B-ALL. To better understand the oncogenic mechanisms by which these alterations might promote B-ALL and to develop an in vivo preclinical model of relapsed B-ALL, we engineered mouse strains with induced somatic KrasG12D pathway activation and/or loss of Ink4a/Arf during early stages of B-cell development. Although constitutive activation of KrasG12D in B cells induced prominent transcriptional changes that resulted in enhanced proliferation, it was not sufficient by itself to induce development of a high-grade leukemia/lymphoma. Instead, in 40% of mice, these engineered mutations promoted development of a clonal low-grade lymphoproliferative disorder resembling human extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue or lymphoplasmacytic lymphoma. Interestingly, loss of the Ink4a/Arf locus, apart from reducing the number of apoptotic B cells broadly attenuated KrasG12D-induced transcriptional signatures. However, combined Kras activation and Ink4a/Arf inactivation cooperated functionally to induce a fully penetrant, highly aggressive B-ALL phenotype resembling high-risk subtypes of human B-ALL such as BCR-ABL and CRFL2-rearranged. Ninety percent of examined murine B-ALL tumors showed loss of the wild-type Ink4a/Arf locus without acquisition of highly recurrent cooperating events, underscoring the role of Ink4a/Arf in restraining Kras-driven oncogenesis in the lymphoid compartment. These data highlight the importance of functional cooperation between mutated Kras and Ink4a/Arf loss on B-ALL.
•Ras pathway activation cooperates with Ink4a/Arf locus deletion in B cells to induce a fully penetrant lymphoma/leukemia phenotype in mice.•These tumors resemble high-risk subtypes of human B-ALL, providing a convenient and highly reproducible model of refractory B-ALL. |
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ISSN: | 2473-9529 2473-9537 |
DOI: | 10.1182/bloodadvances.2017012211 |