Comprehensive review of JAK inhibitors in myeloproliferative neoplasms

Sonbol, Mohamad Bassam; Firwana, Belal; Zarzour, Ahmad; Morad, Mohammad Reza; Rana, Vishal; Tiu, Ramon V.

doi:10.1177/2040620712461047

Cited by 91 publications

(72 citation statements)

References 94 publications

(196 reference statements)

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“…Most patients with chronic JAK2 inhibitor treatment failed to reach molecular and pathologic remissions (6). Consistent with these observations, several reports showed variable efficacies of JAK2 inhibitors on the overall disease burden in mouse models (7,8). These studies indicate that targeting JAK2 alone may not be sufficient to treat the disease.…”

Section: Introductionmentioning

confidence: 65%

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Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

Zhao¹,

Mei²,

Cao³

et al. 2017

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 65%

“…However, distinct from the targeted therapy of BCR-ABL-positive chronic myelogenous leukemia, JAK2 is indispensable for normal hematopoiesis. Therefore, significant side effects including anemia and thrombocytopenia were inevitable when high doses were attempted (7). In addition, JAK2 inhibitor is not curative for the disease.…”

Section: Introductionmentioning

confidence: 99%

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

Zhao¹,

Mei²,

Cao³

et al. 2017

Journal of Clinical Investigation

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“…These data suggest that JAK1/2 inhibitors may have therapeutic efficacy for NKTCL and gd-PTCL patients with the mutations. This may have immediate clinical implication as JAK1/2 inhibitors are already approved for myeloproliferative disorders 21,22 so they are available for trials in NKTCL or gd-PTCL patients while STAT3 and STAT5B inhibitors are still not clinically available. Further development of small-molecule inhibitors targeting STAT3 or STAT5B dimerization or DNA binding may synergize with JAK1/2 inhibitors to improve the outcome in these diseases with currently dismal prognosis.…”

Section: Resultsmentioning

confidence: 99%

Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

et al. 2015

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Lymphomas arising from NK or gd-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n ¼ 51), gd-T-cell lymphomas (n ¼ 43) and their cell lines (n ¼ 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gd-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.

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“…Loss of JH2 ATP binding abrogates hyperactivation of mutant JAK2 in cells and in vivo while leaving wild-type JAK2 largely unaffected. Current pharmacological interventions at JAKs target JH1, and although these inhibitors have brought important advances in the treatment of PMF and PV patients, they are unable to eradicate the disease and they also affect wild-type JAKs (38). Targeting JH2 with conformation-specific ATP binding site inhibitors may give rise to novel pharmacological compounds able to allosterically inhibit pathogenic JAK activity.…”

Section: Discussionmentioning

confidence: 99%

ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation

Hammarén

Ungureanu

Grisouard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

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Pseudokinases lack conserved motifs typically required for kinase activity. Nearly half of pseudokinases bind ATP, but only few retain phosphotransfer activity, leaving the functional role of nucleotide binding in most cases unknown. Janus kinases (JAKs) are nonreceptor tyrosine kinases with a tandem pseudokinase-kinase domain configuration, where the pseudokinase domain (JAK homology 2, JH2) has important regulatory functions and harbors mutations underlying hematological and immunological diseases. JH2 of JAK1, JAK2, and TYK2 all bind ATP, but the significance of this is unclear. We characterize the role of nucleotide binding in normal and pathogenic JAK signaling using comprehensive structure-based mutagenesis. Disruption of JH2 ATP binding in wildtype JAK2 has only minor effects, and in the presence of type I cytokine receptors, the mutations do not affect JAK2 activation. However, JH2 mutants devoid of ATP binding ameliorate the hyperactivation of JAK2 V617F. Disrupting ATP binding in JH2 also inhibits the hyperactivity of other pathogenic JAK2 mutants, as well as of JAK1 V658F, and prevents induction of erythrocytosis in a JAK2 V617F myeloproliferative neoplasm mouse model. Molecular dynamic simulations and thermal-shift analysis indicate that ATP binding stabilizes JH2, with a pronounced effect on the C helix region, which plays a critical role in pathogenic activation of JAK2. Taken together, our results suggest that ATP binding to JH2 serves a structural role in JAKs, which is required for aberrant activity of pathogenic JAK mutants. The inhibitory effect of abrogating JH2 ATP binding in pathogenic JAK mutants may warrant novel therapeutic approaches.T he Janus kinases (JAK1-3, TYK2) are a family of nonreceptor tyrosine kinases with essential functions in the regulation of hematopoiesis, the immune system, and cellular metabolism. JAKs interact specifically with various cytokine receptors and couple cytokine binding to cytoplasmic signaling cascades, including the signal transducers and activators of transcription (STAT) pathway. JAKs consist of an N-terminal FERM domain, an SH2-like (Src homology 2) domain, a pseudokinase domain (JAK homology 2, JH2), and the C-terminal tyrosine kinase domain (JH1). JH2 mediates critical regulatory functions in JAKs and primarily serves to inhibit basal JH1 activity. Experimental deletion of JH2 increases JH1 activity in full-length JAK in the absence of stimulation (1-3), and in recombinant systems addition of JH2 suppresses JH1 activity (4-6). JH2 is, however, also required for ligand-induced activation of full-length JAKs in cell (1-3, 6, 7). The regulatory functions of JH2 are corroborated by the multitude of human disease mutations identified in the domain. The most common JAK2 mutation, V617F, leads to cytokine-independent signaling through the exclusively JAK2-dependent homotypic receptors for erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), and thrombopoietin (8). The V617F mutation is found in ∼95% of patients with polycythemia vera (PV) (9...

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Comprehensive review of JAK inhibitors in myeloproliferative neoplasms

Cited by 91 publications

References 94 publications

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasms

Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells

ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation

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