JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]

Publication Date:
2018-06-20
Publisher:
Cold Spring Harbor Laboratory Press
Print ISSN:
0890-9369
Topics:
Biology
Published by:
http://www.cshlpress.com/
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autor Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
beschreibung Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
citation_standardnr 6287706
datenlieferant ipn_articles
feed_id 1644
feed_publisher Cold Spring Harbor Laboratory Press
feed_publisher_url http://www.cshlpress.com/
insertion_date 2018-06-20
journalissn 0890-9369
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher Cold Spring Harbor Laboratory Press
quelle Genes & Development
relation http://genesdev.cshlp.org/cgi/content/short/32/11-12/849?rss=1
search_space articles
shingle_author_1 Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
shingle_author_2 Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
shingle_author_3 Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
shingle_author_4 Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
shingle_catch_all_1 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_2 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_3 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_catch_all_4 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
Kim, S.-K., Knight, D. A., Jones, L. R., Vervoort, S., Ng, A. P., Seymour, J. F., Bradner, J. E., Waibel, M., Kats, L., Johnstone, R. W.
Cold Spring Harbor Laboratory Press
0890-9369
08909369
shingle_title_1 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
shingle_title_2 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
shingle_title_3 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
shingle_title_4 JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
timestamp 2025-06-30T23:35:39.898Z
titel JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
titel_suche JAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias [Research Papers]
topic W
uid ipn_articles_6287706