Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance

Kesarwani, Meenu; Huber, Erika; Kincaid, Zachary; Evelyn, Chris R.; Biesiada, Jacek; Rance, Mark; Thapa, Mahendra; Shah, Neil P.; Meller, Jarosław; Zheng, Yi; Azam, Mohammad

doi:10.1038/srep14538

Cited by 46 publications

(65 citation statements)

References 73 publications

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“…Furthermore, the inhibitory response of an ATP-competitive JAK inhibitor could be overcome by increasing the extracellular glucose concentration, which translates into increased glycolytic throughput under conditions of IFN-γ stimulation. Indeed, as an ATP-dependent kinase ( Kesarwani et al, 2015 ), the activity of JAK increases as a function of intracellular ATP concentration until a plateau is reached. While aerobic glycolytic throughput can upregulate JAK activity by providing ATP, the initial activation of JAK is still required and relies on IFN-γ-induced receptor dimerization.…”

Section: Discussionmentioning

confidence: 99%

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

et al. 2018

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Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.

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Section: Discussionmentioning

confidence: 99%

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

et al. 2018

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“…The cells were incubated for 60 hours. Cell viability and immunoblottings were performed as described earlier ( 26 ).…”

Section: Methodsmentioning

confidence: 99%

Enhanced MAPK signaling is essential for CSF3R-induced leukemia

et al. 2016

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Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone can not induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.

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“…Saturation mutagenesis studies in murine cell line with RUX have demonstrated the emergence of second site mutations within JAK2 . These mutations conferred resistance to JAKi by a number of agents including RUX [82, 83]. However, it is not clear that this is a relevant phenomenon which is occurring in MPN patients [84] and persisting clones demonstrate the absence of second site mutations in the presence of JAKi [85].…”

Section: Main Textmentioning

confidence: 99%

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

et al. 2018

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The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

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Targeting substrate-site in Jak2 kinase prevents emergence of genetic resistance

Cited by 46 publications

References 73 publications

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

Enhanced MAPK signaling is essential for CSF3R-induced leukemia

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

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