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Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application

Muhammad Furqan, Nikhil Mukhi, Byung Lee and 1 more

Biomarker Research · 2013 · Review

doi:10.1186/2050-7771-1-5

Abstract

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK–STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway is one of the critical intracellular signaling cascades in transduction of extracellular signals to the nucleus to control gene expression. A variety of cytokines and growth factors complete their physiological tasks through JAK-STAT pathway, including hematopoiesis, immune-regulation, fertility, lactation, growth and embryogenesis.

JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. These kinases bind to the juxta-membrane region of cytokine receptors. Each molecule contains seven JAK homology domains (JH1-7). The carboxyl JH1 domain contains the catalytic activity, whereas N-terminal JH7 domain is responsible for receptor binding. JH2 domain has significant homology to JH1 but lacks enzymatic activity and therefore is a pseudo-kinase domain. Binding of a ligand to its receptor results in receptor dimerization, leading to activation of the JAK kinase activity. Subsequently activated JAKs phosphorylate cytoplasmic domain of the receptor. Activated JAK-cytokine receptor complex recruits and phosphorylates specific cytoplasmic transcription factors called STAT proteins. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Phosphorylation of specific STAT proteins results in their dimerization and subsequent translocation into the nucleus to interact with various regulatory elements for gene expression (Figure 1).

Regulation of JAK-STAT pathway

Three major mechanisms have been implicated to negatively regulate the JAK-STAT pathway. Figure 1 depicts the positive and negative regulation of the JAK-STAT pathway.

Tyrosine phosphatases

Src homology-2 (SH2) containing tyrosine phosphatase and CD45 tyrosine phosphatase play a major role in modulating JAK-STAT pathway. SH2 containing tyrosine phosphatases include SHP1 and SHP2 (shatterproof 1 & 2). Their SH2 domains allow attachment to the phospho-tyrosine residues present on activated receptors, JAKs or STAT proteins, leading to dephosphorylation of the substrates. SHP1 is mainly expressed in hematopoietic cells, epithelial and smooth muscle cells whereas SHP2 is ubiquitous. The expression of SHP1 gene was found to be silenced by promoter hypermethylation in various hematological malignancies. CD45 transmembrane tyrosine phosphatase is the second type of tyrosine phosphatase that negatively regulates JAK-STAT pathway. CD45, the leukocyte common antigen, is expressed in hematopoietic cells. It has two phosphatase domains in its intracellular region, though only one is active. Mice deficient for CD45 show hyper-activation of JAK1 and JAK3.

Protein inhibitors of activated STATs (PIAS)

PIAS family consists of PIAS1, PIAS3, PIASx and PIASy. Biochemical assays have shown that PIAS3 and PIASx interact with STAT3 and STAT4 respectively, while PIAS1 and PIASy with STAT1. PIAS1 and PIAS3 exert negative regulation by blocking the DNA binding of STAT1 and STAT3, respectively. On the other hand, PIASx and PIASy repress the transcriptional activity of STAT1 and STAT4 by recruiting co-repressor molecules such as histone deacetylases.

Suppressors of cytokine signaling (SOCS) proteins

The suppressor of cytokine signaling (SOCS) family is composed of SOCS-1 to SOCS-7 and cytokine-inducible SH2-containing protein (CIS). SOCS proteins are cytokine-induced negative feedback-loop regulators of JAK-STAT signaling. Each member protein in this family has a central SH2 domain, variable amino-terminal domain and a carboxy-terminal of 40 amino acids module known as SOCS box. The central SH2 domain directs the target binding of each CIS/SOCS protein. Three mechanisms have been proposed by which a SOCS protein provides negative modulation. First, SOCS binds the phospho-tyrosine residues on the receptors and physically blocks the STATs from binding to its receptors. Second, SOCS proteins can bind directly to its specific JAKs or to the receptors and inhibit the corresponding JAK kinase activity. Third, SOCS associate with the elongin BC complex and cullin 2, accelerating the ubiquination of JAKs and presumably the receptors.

Endosomal degradation of JAK/receptor complex through receptor mediated endocytosis appears to be another mechanism involved in the regulation of the pathway. STAT5ß dimerizes with the full-length, wild-type protein, STAT5α, upon activation. This leads to negative regulation of the JAK-STAT signaling cascade in addition to the major mechanisms described above.

JAK-STAT pathway and hematological malignancies

Dysregulation in JAK-STAT pathway have been described in a variety of hematological malignancies, especially in myeloid disorders. These events may play key roles in initiation and progression of respective diseases.

Ph negative MPNs

Short interfering RNA and JAK2 inhibitor (AG490) have been used to study the activity of JAK2. JAK2 was shown to be central to the erythropoietin-independent erythroid proliferation in polycythemia vera (PV). A common mutation (V617F) in the JH2 pseudo-kinase domain of JAK2 was shown in 80% of the patients. This results in constitutive activation of STAT5 and a malignant phenotype. Other investigators confirmed the fact and showed that 30-50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) also harbor the same mutation.

Allelic burden of JAK2V617F was found to play an important role in determining a distinct clinico-pathologic phenotype from the same mutation. It is suggested by the fact that homozygous JAK2V617F mutation is 30% in PV compared to 2-4% in ET. Transgenic mouse models and clinical cases support the gene-dosage model for MPN pathogenesis. It was observed that high allele burden leads to PV phenotype, whereas reduction in allelic burden leads to ET.

In patients with PV who are negative for JAK2V617F, Scott et al., used a candidate gene approach to search for alleles that can activate JAK signaling. Their work demonstrated at least 8 distinct mutations involving residues 538 to 543 in exon 12 region of JAK2.

Irrespective of JAK2V617F status, patients with PV exhibits high STAT3 and 5 activities, patients with ET have high STAT3 activity, whereas patients with PMF showed low activities of both STAT3 and 5. It is evident that preferential activation of JAK2–STAT5 or JAK2–STAT3 signaling determines PV, ET and PMF phenotype. However patients with JAK2V617F-negative ET or PMF may harbor mutations in other genes in JAK–STAT pathway.

Atypical MPNs

Rare JAK2 gene rearrangement can result in atypical form of chronic myeloid leukemia (aCML). These gene rearrangements include PCM1-JAK2, TEL-JAK2 and BCR-JAK2. Rarely, JAK2V617F mutation can present phenotypically as chronic myelomonocytic leukemia /aCML.

PCM1-JAK2 gene rearrangement was discovered in the translocation, t(8;9)(p22;p24). It is reported in few cases with atypical CML, chronic eosinophilic leukemia, AML (M2, M6), pre B-ALL and T-cell lymphoma.

T-cell lymphoma and leukemia

JAK1 gene plays a unique role in lymphohematopoiesis. Flex et al., showed several acquired JAK1 missense mutations in adult lymphoblastic leukemia, especially in T-cell precursor type where it accounted for 18% of the cases. It was associated with advanced age and poor prognosis.

Translocation between short-arm of chromosome 9 (harboring JAK2 gene) and 12, t(9;12)(p24;p13) results in the formation of a fusion protein, TEL-JAK2. This results in constitutive JAK2 activation. It was found in a case of childhood T-cell acute lymphoblastic leukemia and in a case with pre-B-cell ALL.

Adult T-cell Leukemia (HTLV-1 positive)

Human T-cell lymphotropic virus-1 encoded Tax protein suppresses apoptosis through constitutive activation of the NFκB pathway. This is sufficient for immortalization of CD4+ lymphocytes. HTLV-1 infected T-cells over-express IL-2, IL-15 as well as IL-2 and IL-15 receptors by Tax-induced NFκB activation. These in turn activate JAK3-STAT5 pathway leading to lymphocyte proliferation and adult T-cell lymphoma /leukemia.

T-cell Large Granular Lymphocytic Leukemia, Anaplastic Large cell Lymphoma, Angioimmunoblastic Lymphoma and Sezary Syndrome

Dysregulation of STAT proteins also contributes to the pathogenesis of various types of lymphoid malignancies. Schade et al., reported increase activity of STAT3 in T-cell large granular lymphocytic leukemia. Constitutive activation of STAT3 & 5 was also found to be an important event in the pathogenesis of anaplastic large cell lymphoma, T-cell angioimmunoblastic lymphoma and Sezary syndrome.

Acute lymphoblastic leukemia

Kearney et al., performed sequencing of exon 14 of JAK2 gene in patients with Down syndrome associated ALL. An acquired somatic point mutation invovling residue R683 was found in 28% of cases. A different mutation in JAK2 gene in a patient with Down syndrome associated precursor B-cell lymphoblastic leukemia was reported by Malinge et al., This mutation was in-frame deletion of five-amino acid residues from position 682 to 686, named as IREED mutation, in the pseudokinase domain of JAK2. This IREED mutant remains constitutively active and induces cytokine independence in Ba/F3 cells.

Another JAK2 mutation involves fusion with SSBP2 in t(5;9)(q14.1;p24.1) translocation. It was detected in a patient with pre B-cell ALL.

Chronic lymphocytic leukemia

Constitutive activation of STAT1 & 3 was noticed in transformed B-cells in patients with chronic lymphocytic leukemia (CLL). Activated STAT1 & 3 proteins in malignant B-cells were phosporylated at serine instead of tyrosine residue. It remained uncertain whether activated STAT involved directly in the pathophysiology of this disease or represented a pure epi-phenomenon.

Primary mediastinal B-cell lymphoma

A bi-allelic mutation in SOCS-1 has been reported in primary mediastinal B-cell lymphoma. This results in delayed turnover of phosphorylated JAK2 and increased activity of STAT5, which may explain the uncontrolled growth of malignant cells.

Hodgkin lymphoma

Gene rearrangement by translocation involving JAK2, t(4;9)(q21;p24), has been reported in 2 cases of classic Hodgkin lymphoma by a group from Belgium. This gene re-arrangement creates a novel fusion product, SEC31A-JAK2. This oncogenic SEC31A-JAK2 has constitutively active tyrosine kinase activity. Mutations of SOCS-1 have also been identified in Hodgkin lymphoma.

Acute myeloid leukemia

Increased activity of STAT3 has been reported in 20-50% of AML patients while STAT5 and STAT1 activation is uncommon. The pathologic value of activated STAT3 in AML is unclear. It was also found in acute promyelocytic leukemia (APL). An interstitial deletion within chromosome 17 has been described to result in STAT5b-RARα fusion protein. This was implied to serve as a key pathogenic event in a patient with APL. Transformation from severe congenital neutropenia due to truncated G-CSF receptor to AML also involves dysregulation of STAT proteins. Truncated G-CSF receptor lacks a crucial binding site for SOCS-3, thus relieving inhibition of STAT5, but not of STAT3. This favors myeloid proliferation over differentiation. These truncated receptors are also resistant to down modulation through ubiquination.

Rare point mutations, one in JAK2 (T875N) and three in JAK3 (A572V, V722I, P132T), have been described in patients with acute megakaryocytic luekemia. PCM1-JAK2 gene rearrangement mentioned above was found in M2 and M6 AML.

Myelodysplastic syndrome (MDS)

Perturbation in JAK-STAT pathway is rare in MDS. Only 4.2% patients with MDS were found to harbor JAK2V617F mutation in a large screening series. Of interest is a disease entity called refractory anemia with ringed sideroblast associated with marked thrombocytosis (RARS-t). These patients have features of both MDS and MPN. It was recently shown that 6 out of 9 (67%) patients with RARS-t have JAK2V617F mutation.

Multiple myeloma

Constitutive expression of STAT3 has been seen frequently in patients with multiple myeloma and lymphoma. However, overexpression of anti-apoptotic proteins of Bcl-2, Bcl-XL and Mcl-1 may not rely on STAT3 activation. The role of this pathway in pathogenesis of myeloma remains to be determined.

Novel inhibitors of JAK-STAT pathway

The specific and profound involvement of JAK-STAT pathway in various hematological malignancies, especially Bcr-Abl negative MPNs, makes them ideal targets for pharmacological intervention. Several strategies have been proposed to inhibit or modulate this pathway. JAK inhibitors are among the first successful agents reaching clinical application.

JAK inhibitors

There are at least 10 different JAK inhibitors undergoing various phases of clinical trials (Table 1). Ruxolitinib (Jakafi manufactured by Incyte, Inc) has been approved by FDA for patients with intermediate- to high- risk primary or secondary myelofibrosis.

Ruxolitinib

Ruxolitinib (INCB018424) is a non-selective JAK1 & 2 inhibitor. Multiple phase I/II studies in various hematological malignancies are underway. Among these, results are most mature for PMF and post –ET /PV myelofibrosis.

Phase I/II studies

A total of 153 patients with myelofibrosis were recruited in a phase I/II study. Dose limiting toxicity was thrombocytopenia with maximum tolerated dose of 25 mg twice daily. Effect on JAK2V617F allele burden or bone marrow fibrosis was insignificant. After a longer follow up, it was described that abrupt discontinuation can lead to serious adverse events like acute relapse of constitutional symptoms, rapid and painful enlargement of spleen and shock. By the time of last report on the follow up of these patients 35% of patient died and 10% transformed to leukemia.

Eghtedar et al., reported a phase I/II study of ruxolitinib in patients with relapsed /refractory AML. This study has shown 7% complete remission rate. It was noticed that patients who achieved complete remission were those with post-MPN AML.

Phase III studies

Ruxolitinib has undergone 2 separate randomized controlled trials, referred to as the COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) I & II (Table 2). Patients were randomized between ruxolitinib vs placebo (COMFORT I) or best available therapy (COMFORT II). Patients with PMF or post –ET /PV myelofibrosis must have high or intermediate international prognostic scores, palpable spleen ≥5 cm below the left costal margin, and platelet count equal or greater than 100 × 109 /L. Patients were recruited irrespective of JAK2 gene mutation status. Differences in the design of these trials and major outcomes are summarized in Table 2.

These trials support the palliative role of ruxolitinib which significantly reduced spleen volume and constitutional symptoms. The responses were not specific for JAK2 mutation.

SAR302503 (TG101348)

SAR302503 is a selective JAK2 inhibitor with activity on both wild type and mutant JAK2. Fifty nine patients were enrolled in a multi-center phase I/II trial with high-or- intermediate-risk primary or post-PV/ET myelofibrosis. Patients with platelet count equal or greater than 50 x 109 /L were eligible. Reversible increase in serum amylase was the dose limiting toxicity. Serious adverse events included mainly myelosuppression and gastrointestinal toxicity. A spleen response of 47% was seen after one year of treatment. JAK2V617F allele burden was significantly decreased at 6 months in mutation-positive patients (n = 51; P =.04). The response was higher in patients with allele burden greater than 20% (n = 23; P <.01). A multinational, randomized, placebo controlled phase III trial has been launched recently for patients with high risk myelofibrosis.

Lestaurtinib (CEP701)

Lestaurtinib is an orally available indolocarbazole derivative. It was originally identified as an inhibitor of the neurotropin receptor TrkA. It was found to also inhibit FLT3, JAK2 and JAK3. Due to its strong activity against FLT3, it is under investigation in patients with acute leukemia. A phase I/II study of lestaurtinib was done in 22 patients with JAK2-mutated myelofibrosis. The patients received 80 mg twice-daily. The response rate was 27%. The median duration of response was more than 14 months. However, bone marrow fibrosis or JAK2V617F allele burden was not significantly altered.

In another phase 2 study, lestaurtinib was given to 39 high-risk patients with JAK2V617F-positive PV (n=27) or ET (n=12). After 18 weeks of treatment, a significant decrease in spleen size was reported in 83% of the patients. Six patient developed thrombosis. The increase in the thrombotic events remains a concern for this agent.

CYT387

CYT387 is an ATP-competitive small molecule JAK1/JAK2 inhibitor. It has an IC50 of 11 and 18 nM for JAK1 and JAK2, respectively. Unlike lestaurtinib, CYT387 has significantly less activity against other kinases, including JAK3 (IC50=0.16 μM).

One hundred sixty three patients with high- or intermediate- risk myelofibrosis were enrolled in a phase I/II trial of CYT387. The median duration of treatment was 6.6 months. Dose limiting toxicities included hyper-lipasemia and headaches. Maximum tolerated dose was 300 mg/day. The response rates for reduction of spleen size, anemia, and constitutional symptom were 45%, 50%, and more than 50%, respectively. It is interesting to note that responses were also seen in patients who had previously failed ruxolitinib or SAR302503. Surprisingly, 58% of transfusion-dependent patients became transfusion-independent. Transient light headedness and hypotension were the common adverse events. Treatment-related severe anemia was infrequent (< 1%). This property separates it from ruxolitinib and SAR302503.

SB1518 (pacritinib)

Pacritinib is another orally bioavailable ATP-competitive small molecule inhibitor of JAK2 and the mutant JAK2V617F. It inhibitis JAK-STAT signaling pathway through caspase-dependent apoptosis. In a phase I/II trial, 34 patients with primary or post PV/ET myelofibrosis were enrolled. The median time on study was 8.2 months. Patients with low blood counts were not excluded. Most common adverse events were diarrhea, nausea and vomiting. The primary end point was spleen response, which was 32%. The median duration of spleen response has not been reached at the recent update.

In another phase I trial, 30 patients with relapsed/refractory lymphoma were enrolled. The dose was escalated from 200–600 mg/day. Severe adverse events included cytopenia, internal hemorrhage, various infections and abdominal distention. No patient achieved complete remission. Three patients had partial remission and 13 patients had stable disease. Phase II trial is ongoing.

LY2784544

LY2784544 is a selective mutant JAK2 kinase inhibitor with an IC50 of 68 nM. This molecule selectively inhibited the JAK2 V617F-STAT5 signaling at a concentration that was 41-fold lower than that needed for the wild type (WT) JAK2 signaling (IC50 = 55 nM for V617F vs. 2260 nM for WT ). A phase I/II trial recruited 19 patients with Ph negative MPN. Maximum tolerated dose was 120 mg/day. Spleen response was 22% for patients with MF. JAK2V617F allele burden was not significantly decreased. Main adverse events included diarrhea, nausea, anemia and electrolyte imbalance.

XL019

XL019 represents another oral selective JAK2 inhibitor (IC50= 2nM for JAK2, 130 nM for JAK1, 250 nM for JAK3, 340 nM for TYK2). A phase I study recruited 21 patients with myelofibrosis. 16 patients had JAK2V617F, one had MPL W515F. Dose ranged from 25 to 300 mg. Surprisingly, there was no hematological adverse events. Improvement in clinical outcome observed in all patients with JAK2V617F or MPL activating mutations. Despite these results, further development of clinical trials using XL019 was aborted out of the concerns for neurologic toxicities.

NS-018, BMS-911543 and AZD1480

These JAK inhibitors are also selective JAK inhibitors at very early stage of drug development. NS-018 was shown to be highly selective against JAK2 with IC50 <1 nM. It had 30–50 fold greater selectivity for JAK2 over other JAK-family kinases, such as JAK1, JAK3 and Tyk2. BMS-911543 is a functionally selective JAK2 inhibitor. AZD1480 has been shown both in vitro and in vivo to inhibit the growth of multiple malignancies by inhibiting phosphorylation of JAK2, STAT3 and MAPK signaling proteins. Clinical investigations on these agents are underway.

Conclusion and future directions

Currently the benefits of therapy with JAK inhibitors in MPNs are palliative in nature. This is suggested by inability of ruxolitinib to influence the natural history of the diseases and by the fact that the responses are unrelated to JAK mutation status. JAK2V617F mutation may be a key event but not necessarily a primary factor driving the tumorigenesis of MPNs. Other molecular events may precede the acquisition of JAK2V617F mutation in these disorders. Novel selective JAK2 inhibitors are the active focus for further clinical investigations.

In addition to JAK inhibitors, targeting STAT signaling is emerging as an attractive approach to inhibit tumorigenesis. Various strategies have been employed to influence STAT signaling at multiple levels, though these approaches are still at early stage and only supported by pre-clinical data. Further advancement in understanding the molecular events and refining the targets can potentially lead to further clinical benefit. Simultaneous intervention at multiple levels of the signaling cascade by combining different targeting agents may offer additional advantages and is worthwhile studying.

Competing interest

The authors have no relevant conflicts of interest.

Authors’ contributions

All authors have contributed to data preparation, drafting and revising the manuscripts. All authors have read and approved the final manuscript.

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    Murati A Gelsi-Boyer V Adelaide J Perot C Talmant P Giraudier S Lode L Letessier A Delaval B Brunel V PCM1-JAK2 fusion in myeloproliferative disorders and acute erythroid leukemia with t(8;9) translocationLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2005 19916921696

    Not in our library10.1038/sj.leu.2403879

  36. 36.

    Reiter A Walz C Watmore A Schoch C Blau I Schlegelberger B Berger U Telford N Aruliah S Yin JA The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2Cancer Res2005 65726622667

    Not in our library10.1158/0008-5472.can-04-4263

  37. 37.

    Lacronique V Boureux A Valle VD Poirel H Quang CT Mauchauffe M Berthou C Lessard M Berger R Ghysdael J A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemiaScience1997 278534113091312

    Not in our library10.1126/science.278.5341.1309

  38. 38.

    Ratner L JAK blockade and HTLVBlood2011 117617711772

    Not in our library10.1182/blood-2010-12-322008

  39. 39.

    Schade AE Wlodarski MW Maciejewski JP Pathophysiology defined by altered signal transduction pathways: the role of JAK-STAT and PI3K signaling in leukemic large granular lymphocytesCell Cycle2006 52225712574

    Not in our library10.4161/cc.5.22.3449

  40. 40.

    Meier C Hoeller S Bourgau C Hirschmann P Schwaller J Went P Pileri SA Reiter A Dirnhofer S Tzankov A Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomasModern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc2009 223476487

    Not in our library10.1038/modpathol.2008.207

  41. 41.

    Zhang Q Nowak I Vonderheid EC Rook AH Kadin ME Nowell PC Shaw LM Wasik MA Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndromeProc Natl Acad Sci U S A1996 931791489153

    Not in our library10.1073/pnas.93.17.9148

  42. 42.

    Kearney L Gonzalez De Castro D Yeung J Procter J Horsley SW Eguchi-Ishimae M Bateman CM Anderson K Chaplin T Young BD Specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukemiaBlood2009 1133646648

    Not in our library10.1182/blood-2008-08-170928

  43. 43.

    Malinge S Ben-Abdelali R Settegrana C Radford-Weiss I Debre M Beldjord K Macintyre EA Villeval JL Vainchenker W Berger R Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemiaBlood2007 109522022204

    Not in our library10.1182/blood-2006-09-045963

  44. 44.

    Poitras JL Dal Cin P Aster JC Deangelo DJ Morton CC Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemiaGenes Chromosomes Cancer2008 4710884889

    Not in our library10.1002/gcc.20585

  45. 45.

    Frank DA Mahajan S Ritz J B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residuesJ Clin Invest1997 1001231403148

    Not in our library10.1172/jci119869

  46. 46.

    Melzner I Bucur AJ Bruderlein S Dorsch K Hasel C Barth TF Leithauser F Moller P Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma lineBlood2005 105625352542

    Not in our library10.1182/blood-2004-09-3701

  47. 47.

    Van Roosbroeck K Cox L Tousseyn T Lahortiga I Gielen O Cauwelier B De Paepe P Verhoef G Marynen P Vandenberghe P JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphomaBlood2011 1171540564064

    Not in our library10.1182/blood-2010-06-291310

  48. 48.

    Weniger MA Melzner I Menz CK Wegener S Bucur AJ Dorsch K Mattfeldt T Barth TF Moller P Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulationOncogene2006 251826792684

    Not in our library10.1038/sj.onc.1209151

  49. 49.

    Ghoshal Gupta S Baumann H Wetzler M Epigenetic regulation of signal transducer and activator of transcription 3 in acute myeloid leukemiaLeuk Res2008 32710051014

    Not in our library10.1016/j.leukres.2007.11.035

  50. 50.

    Steensma DP McClure RF Karp JE Tefferi A Lasho TL Powell HL DeWald GW Kaufmann SH JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplainedLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2006 206971978

    Not in our library10.1038/sj.leu.2404206

  51. 51.

    Maurer AB Wichmann C Gross A Kunkel H Heinzel T Ruthardt M Groner B Grez M The Stat5-RARalpha fusion protein represses transcription and differentiation through interaction with a corepressor complexBlood2002 99826472652

    Not in our library10.1182/blood.v99.8.2647

  52. 52.

    Constantinescu SN Girardot M Pecquet C Mining for JAK-STAT mutations in cancerTrends Biochem Sci2008 333122131

    Not in our library10.1016/j.tibs.2007.12.002

  53. 53.

    Levine RL Loriaux M Huntly BJ Loh ML Beran M Stoffregen E Berger R Clark JJ Willis SG Nguyen KT The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemiaBlood2005 1061033773379

    Not in our library10.1182/blood-2005-05-1898

  54. 54.

    Szpurka H Tiu R Murugesan G Aboudola S Hsi ED Theil KS Sekeres MA Maciejewski JP Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutationBlood2006 108721732181

    Not in our library10.1182/blood-2006-02-005751

  55. 55.

    Zl W Yq S Yf S Zhu J High nuclear expression of STAT3 is associated with unfavorable prognosis in diffuse large B-cell lymphomaJ Hematol Oncol2011 4131

    Not in our library10.1186/1756-8722-4-31

  56. 56.

    Quintanilla-Martinez L Kremer M Specht K Calzada-Wack J Nathrath M Schaich R Hofler H Fend F Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive eventsAm J Pathol2003 162514491461

    Not in our library10.1016/s0002-9440(10)64278-2

  57. 57.
    Development of a highly sensitive method for detection of JAK2V617F · 2011
    Not checked
  58. 58.

    Tognon R Gasparotto E Neves R Nunes N Ferreira A Palma P Kashima S Covas D Santana M Souto E Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and MyelofibrosisJ Hematol Oncol2012 512

    Not in our library10.1186/1756-8722-5-2

  59. 59.

    Zhao W Du Y Ho W Fu X Zhao Z JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell linesExperimental Hematology & Oncology2012 1115

    Not in our library10.1186/2162-3619-1-15

  60. 60.

    Passamonti F Maffioli M Caramazza D New generation small-molecule inhibitors in myeloproliferative neoplasmsCurr Opin Hematol2012 192117123

    Not in our library10.1097/moh.0b013e32834ff575

  61. 61.

    Randhawa J Ostojic A Vrhovac R Atallah E Verstovsek S Splenomegaly in myelofibrosis–new options for therapy and the therapeutic potential of Janus kinase 2 inhibitorsJ Hematol Oncol2012 5143

    Not in our library10.1186/1756-8722-5-43

  62. 62.

    Verstovsek S Kantarjian H Mesa RA Pardanani AD Cortes-Franco J Thomas DA Estrov Z Fridman JS Bradley EC Erickson-Viitanen S Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosisN Eng J Med2010 3631211171127

    Not in our library10.1056/nejmoa1002028

  63. 63.

    Tefferi A Litzow MR Pardanani A Long-term outcome of treatment with ruxolitinib in myelofibrosisN Eng J Med2011 3651514551457

    Not in our library10.1056/nejmc1109555

  64. 64.

    Verstovsek S Kantarjian HM Estrov Z Cortes JE Thomas DA Kadia T Pierce S Jabbour E Borthakur G Rumi E Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controlsBlood2012 120612021209

    Not in our library10.1182/blood-2012-02-414631

  65. 65.

    Eghtedar A Verstovsek S Estrov Z Burger J Cortes J Bivins C Faderl S Ferrajoli A Borthakur G George S Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemiaBlood2012 1192046144618

    Not in our library10.1182/blood-2011-12-400051

  66. 66.

    Harrison C Kiladjian JJ Al-Ali HK Gisslinger H Waltzman R Stalbovskaya V McQuitty M Hunter DS Levy R Knoops L JAK inhibition with ruxolitinib versus best available therapy for myelofibrosisN Eng J Med2012 3669787798

    Not in our library10.1056/nejmoa1110556

  67. 67.

    Verstovsek S Mesa RA Gotlib J Levy RS Gupta V DiPersio JF Catalano JV Deininger M Miller C Silver RT A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosisN Eng J Med2012 3669799807

    Not in our library10.1056/nejmoa1110557

  68. 68.

    Wernig G Kharas MG Okabe R Moore SA Leeman DS Cullen DE Gozo M McDowell EP Levine RL Doukas J Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia veraCancer Cell2008 134311320

    Not in our library10.1016/j.ccr.2008.02.009

  69. 69.

    Lasho TL Tefferi A Hood JD Verstovsek S Gilliland DG Pardanani A TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patientsLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2008 22917901792

    Not in our library10.1038/leu.2008.56

  70. 70.

    Pardanani A Gotlib JR Jamieson C Cortes JE Talpaz M Stone RM Silverman MH Gilliland DG Shorr J Tefferi A Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosisJournal of clinical oncology: official journal of the American Society of Clinical Oncology2011 297789796

    Not in our library10.1200/jco.2010.32.8021

  71. 71.

    Santos FP Kantarjian HM Jain N Manshouri T Thomas DA Garcia-Manero G Kennedy D Estrov Z Cortes J Verstovsek S Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosisBlood2010 115611311136

    Not in our library10.1182/blood-2009-10-246363

  72. 72.

    Moliterno AR Hexner E Roboz GJ Carroll M Luger S Mascarenhas J Hoffman R Bensen-Kennedy DM An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive PV and ET: Update of 39 Enrolled PatientsASH Annual Meeting Abstracts2009 11422753

    Not in our library

  73. 73.

    Sparidans RW Durmus S Xu N Schinkel AH Schellens JH Beijnen JH Liquid chromatography-tandem mass spectrometric assay for the JAK2 inhibitor CYT387 in plasmaJ Chromatogr B Analyt Technol Biomed Life Sci2012 895–896174177

    Not in our library10.1016/j.jchromb.2012.03.021

  74. 74.

    Monaghan KA Khong T Burns CJ Spencer A The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cellsLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2011 251218911899

    Not in our library10.1038/leu.2011.175

  75. 75.

    Tyner JW Bumm TG Deininger J Wood L Aichberger KJ Loriaux MM Druker BJ Burns CJ Fantino E Deininger MW CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasmsBlood2010 1152552325240

    Not in our library10.1182/blood-2009-05-223727

  76. 76.

    Pardanani A Lasho T Smith G Burns CJ Fantino E Tefferi A CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patientsLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2009 23814411445

    Not in our library10.1038/leu.2009.50

  77. 77.

    Pardanani A Gotlib J Gupta V Roberts AW Wadleigh M Sirhan S Litzow MR Hogan WJ Begna K Smith G An Expanded Multicenter Phase I/II Study of CYT387, a JAK- 1/2 Inhibitor for the Treatment of MyelofibrosisASH Annual Meeting Abstracts2011 118213849

    Not in our library

  78. 78.

    Pardanani AD Caramazza D George G Lasho TL Hogan WJ Litzow MR Begna K Hanson CA McClure RF Bavisotto LM Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosisASCO Meeting Abstracts2011 2915_suppl6514

    Not in our library

  79. 79.

    Hart S Goh KC Novotny-Diermayr V Tan YC Madan B Amalini C Ong LC Kheng B Cheong A Zhou J Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemiaBlood cancer journal2011 111e44

    Not in our library10.1038/bcj.2011.43

  80. 80.

    Poulsen A William A Blanchard S Lee A Nagaraj H Wang H Teo E Tan E Goh KC Dymock B Structure-based design of oxygen-linked macrocyclic kinase inhibitors: discovery of SB1518 and SB1578, potent inhibitors of Janus kinase 2 (JAK2) and Fms-like tyrosine kinase-3 (FLT3)J Comput Aided Mol Des2012 264437450

    Not in our library10.1007/s10822-012-9572-z

  81. 81.

    Hart S Goh KC Novotny-Diermayr V Hu CY Hentze H Tan YC Madan B Amalini C Loh YK Ong LC SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignanciesLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2011 251117511759

    Not in our library10.1038/leu.2011.148

  82. 82.

    William AD Lee AC Blanchard S Poulsen A Teo EL Nagaraj H Tan E Chen D Williams M Sun ET Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6). 1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a potent Janus kinase 2/fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphomaJ Med Chem2011 541346384658

    Not in our library10.1021/jm200326p

  83. 83.

    Komrokji RS Wadleigh M Seymour JF Roberts AW To LB Zhu HJ Mesa RA Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosisASH Annual Meeting Abstracts2011 11821282

    Not in our library

  84. 84.

    Younes A Fanale MA McLaughlin P Copeland A Zhu J de Castro Faria S Phase I Study of a Novel Oral JAK-2 Inhibitor SB1518 In Patients with Relapsed Lymphoma: Evidence of Clinical and Biologic Activity In Multiple Lymphoma SubtypesASH Annual Meeting Abstracts2010 116212830

    Not in our library10.1200/jco.2012.42.5223

  85. 85.

    Verstovsek S Mesa RA Rhoades SK Giles JLK Pitou C Jones E Walgren RA Prchal JT Phase I Study of the JAK2 V617F Inhibitor, LY2784544, in Patients with Myelofibrosis (MF), Polycythemia Vera (PV), and Essential Thrombocythemia (ET)ASH Annual Meeting Abstracts2011 118212814

    Not in our library

  86. 86.

    Shah NP Olszynski P Sokol L Verstovsek S Hoffman R List AF Cortes J Kantarjian HM Gilliland DG Clary DO A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia MyelofibrosisASH Annual Meeting Abstracts2008 1121198

    Not in our library

  87. 87.

    Paquette R Sokol L Shah NP Silver RT List AF Clary DO Bui LA Talpaz M A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Polycythemia VeraASH Annual Meeting Abstracts2008 112112810

    Not in our library

  88. 88.

    Tefferi A JAK inhibitors for myeloproliferative neoplasms: clarifying facts from mythsBlood2012 1191227212730

    Not in our library10.1182/blood-2011-11-395228

  89. 89.

    Nakaya Y Shide K Niwa T Homan J Sugahara S Horio T Kuramoto K Kotera T Shibayama H Hori K Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasmsBlood cancer journal2011 17e29

    Not in our library10.1038/bcj.2011.29

  90. 90.

    Purandare AV McDevitt TM Wan H You D Penhallow B Han X Vuppugalla R Zhang Y Ruepp SU Trainor GL Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2012 262280288

    Not in our library10.1038/leu.2011.292

  91. 91.

    Scuto A Krejci P Popplewell L Wu J Wang Y Kujawski M Kowolik C Xin H Chen L Wang Y The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survivalLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2011 253538550

    Not in our library10.1038/leu.2010.289

  92. 92.

    Derenzini E Lemoine M Buglio D Katayama H Ji Y Davis RE Sen S Younes A The JAK inhibitor AZD1480 regulates proliferation and immunity in Hodgkin lymphomaBlood cancer journal2011 112e46

    Not in our library10.1038/bcj.2011.46

  93. 93.

    Loveless ME Lawson D Collins M Nadella MV Reimer C Huszar D Halliday J Waterton JC Gore JC Yankeelov TE Comparisons of the efficacy of a Jak1/2 inhibitor (AZD1480) with a VEGF signaling inhibitor (cediranib) and sham treatments in mouse tumors using DCE-MRI, DW-MRI, and histologyNeoplasia2012 1415464

    Not in our library10.1593/neo.111478

  94. 94.

    McFarland BC Ma JY Langford CP Gillespie GY Yu H Zheng Y Nozell SE Huszar D Benveniste EN Therapeutic potential of AZD1480 for the treatment of human glioblastomaMol Cancer Ther2011 101223842393

    Not in our library10.1158/1535-7163.mct-11-0480

  95. 95.

    Deshpande A Reddy MM Schade GO Ray A Chowdary TK Griffin JD Sattler M Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasmsLeukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK2012 264708715

    Not in our library10.1038/leu.2011.255

  96. 96.

    Xin H Herrmann A Reckamp K Zhang W Pal S Hedvat M Zhang C Liang W Scuto A Weng S Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480Cancer Res2011 712166016610

    Not in our library10.1158/0008-5472.can-11-1217

  97. 97.

    Mankan AK Greten FR Inhibiting signal transducer and activator of transcription 3: rationality and rationale design of inhibitorsExpert Opin Investig Drugs2011 20912631275

    Not in our library10.1517/13543784.2011.601739

  98. 98.

    Ioannidis S Lamb ML Wang T Almeida L Block MH Davies AM Peng B Su M Zhang HJ Hoffmann E Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)p yrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathwayJ Med Chem2011 541262276

    Not in our library10.1021/jm1011319

  99. 99.

    Hedvat M Huszar D Herrmann A Gozgit JM Schroeder A Sheehy A Buettner R Proia D Kowolik CM Xin H The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumorsCancer Cell2009 166487497

    Not in our library10.1016/j.ccr.2009.10.015

  100. 100.

    Coppelli FM Grandis JR Oligonucleotides as anticancer agents: from the benchside to the clinic and beyondCurr Pharm Des2005 112228252840

    Not in our library10.2174/1381612054546752

  101. 101.

    Jing N Sha W Li Y Xiong W Tweardy DJ Rational drug design of G-quartet DNA as anti-cancer agentsCurr Pharm Des2005 112228412854

    Not in our library10.2174/1381612054546761

  102. 102.

    Nelson EA Sharma SV Settleman J Frank DA A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translationOncotarget2011 26518524

    Not in our library10.18632/oncotarget.296

  103. 103.

    Perrotti D Neviani P Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemiasCancer Metastasis Rev2008 272159168

    Not in our library10.1007/s10555-008-9119-x

  104. 104.

    Redell MS Ruiz MJ Alonzo TA Gerbing RB Tweardy DJ Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitorBlood2011 1172157015709

    Not in our library10.1182/blood-2010-04-280123

  105. 105.

    Santo L Hideshima T Cirstea D Bandi M Nelson EA Gorgun G Rodig S Vallet S Pozzi S Patel K Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomideClinical cancer research: an official journal of the American Association for Cancer Research2011 171032593271

    Not in our library10.1158/1078-0432.ccr-10-3012

  106. 106.

    Turkson J Kim JS Zhang S Yuan J Huang M Glenn M Haura E Sebti S Hamilton AD Jove R Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activityMol Cancer Ther2004 33261269

    Not in our library

  107. 107.

    Hayakawa F Sugimoto K Kurahashi S Sumida T Naoe T A Novel STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition in a Wide Range of Hematopoietic Malignancies without Growth Suppression of Normal Hematopoietic CellsASH Annual Meeting Abstracts2011 11821577

    Not in our library

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