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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
Main Authors: Sewastianik, Tomasz, Jiang, Meng, Sukhdeo, Kumar, Patel, Sanjay S., Roberts, Kathryn, Kang, Yue, Alduaij, Ahmad, Dennis, Peter S., Lawney, Brian, Liu, Ruiyang, Song, Zeyuan, Xiong, Jessie, Zhang, Yunyu, Lemieux, Madeleine E., Pinkus, Geraldine S., Rich, Jeremy N., Weinstock, David M., Mullighan, Charles G., Sharpless, Norman E., Carrasco, Ruben D.
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Language:English
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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.
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2017012211