Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

Kong, Guangyao; Wunderlich, Mark; Yang, David T.; Ranheim, Erik A.; Young, Ken H.; Wang, Jinyong; Chang, Yuh‐Fang; Du, Juan; Liu, Yangang; Tey, Sin-Ruow; Zhang, Xinmin; Juckett, Mark; Mattison, Ryan J.; Damnernsawad, Alisa; Zhang, Jingfang; Mulloy, James C.; Zhang, Jing

doi:10.1172/jci74182

Cited by 47 publications

(45 citation statements)

References 46 publications

(71 reference statements)

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“…57 In contrast, combined MEK and JAK/STAT inhibition in an NRAS G12D/G12D model of MPN significantly improved survival of these mice. 40 Our JMML patient harbors a KRAS mutation, yet ruxolitinib was more effective than MEK inhibition at controlling colony formation of the patient's cells. These data provide a rationale for Stat5 is critical for Nf1-initiated MPN haematologica | 2016; 101 (10)clinical trials combining ruxolitinib with RAS-pathway inhibitors to control activated RAS myeloid neoplasia.…”

Section: Discussionmentioning

confidence: 82%

“…MEK inhibition in mice with Nf1-deficient or Ras-activated MPN led to improvements in disease parameters but failed to eradicate leukemia cells. 24,40 Likewise, MEK inhibition in early phase clinical trials in acute myelogenous leukemia has yielded largely disappointing results. 57 In contrast, combined MEK and JAK/STAT inhibition in an NRAS G12D/G12D model of MPN significantly improved survival of these mice.…”

Section: Discussionmentioning

confidence: 99%

“…40 These findings implicate STAT5 as a potential contributor to the pathogenesis of MPN with activated RAS. Since the therapeutic options in JMML are severely limited, identifying effective drug targets in this devastating disease of infancy is an important clinical priority.…”

Section: Stat5 Is Critical For the Development And Maintenance Of Myementioning

confidence: 93%

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Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

et al. 2016

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

et al. 2016

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“…EdU incorporation was measured 16 h later using the Click-It EdU Pacific Blue flow kit (Invitrogen) as described previously (31). Briefly, Sca1 ϩ cells were enriched using an AutoMACS (Miltenyi).…”

Section: Methodsmentioning

confidence: 99%

Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in Nras/+ Mice

Zhang

Ranheim

Liu

et al. 2015

Journal of Biological Chemistry

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“…115 Finally, recent reports of aberrant DNA methylation contributing to increased risk for relapse 81 has resulted in an EWOG/MDS and Innovative Therapies for Children with Cancer trial using the DNA hypomethylating agent azacitidine for treatment of pediatric patients with newly diagnosed or relapsed high-grade MDS or JMML (EUDRACT no. 2010-022235-10).…”

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confidence: 99%

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

Chang

Dvorak

Loh

2014

Blood

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Juvenile myelomonocytic leukemia (JMML) is a typically aggressive myeloid neoplasm of childhood that is clinically characterized by overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. JMML is categorized as an overlap myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) by the World Health Organization and also shares some clinical and molecular features with chronic myelomonocytic leukemia, a similar disease in adults. Although the current standard of care for patients with JMML relies on allogeneic hematopoietic stem cell transplant, relapse is the most frequent cause of treatment failure. Tremendous progress has been made in defining the genomic landscape of JMML. Insights from cancer predisposition syndromes have led to the discovery of nearly 90% of driver mutations in JMML, all of which thus far converge on the Ras signaling pathway. This has improved our ability to accurately diagnose patients, develop molecular markers to measure disease burden, and choose therapeutic agents to test in clinical trials. This review emphasizes recent advances in the field, including mapping of the genomic and epigenome landscape, insights from new and existing disease models, targeted therapeutics, and future directions.

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Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

Cited by 47 publications

References 46 publications

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in Nras/+ Mice

Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia

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