Persistent Activation of JAK/STAT Signaling Plays an Important Role inin VitroJaki Resistance inTYK2-rearranged B-Cell Acute Lymphoblastic Leukaemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Paniz Tavakoli ◽  
Laura N Eadie ◽  
Susan L Heatley ◽  
John B Bruning ◽  
Deborah L White
Keyword(s):  
Western Blot ◽  
Computational Modeling ◽  
Myeloproliferative Neoplasms ◽  
Resistance Mechanisms ◽  
Kinase Domain ◽  
Janus Kinase ◽  
The Novel ◽  
Clinical Scenarios ◽  
Stat Signaling

Introduction TYK2-rearrangements have recently been detected in high-risk acute lymphoblastic leukemia (HR-ALL) cases and are associated with poor outcome. The resultant fusion protein is predominantly driven by Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. Thus, JAK/TYK2 inhibitors (JAKi) are among the most promising targeted therapeutics against these fusions. This was confirmed in aMYB-TYK2mouse model where the induced aggressive B-ALL was effectively targeted by the novel dual SYK/JAKi, cerdulatinib (cerd) (Tavakoliet al.2020, EHA abstract EP353). Despite the clinical benefit of JAKi in myeloproliferative neoplasms, resistance occurs resulting in relapse. Hence it is necessary to identify potential JAKi-mediated resistance mechanisms inTYK2-rearranged B-ALL patients. This study modeled cerd resistance mechanisms to recapitulate possible clinical scenarios. Methods Ba/F3 pro-B cells were retrovirally transduced with a plasmid construct containing theMYB-TYK2fusion gene isolated from an ALL patient. A cerd resistant line (cerdres) was generated by exposure of Ba/F3-MYB-TYK2cells to increasing concentrations of cerd (up to 3µM; clinically achievable plasma level is 1-2µM) over a period of 151 d. IC50 was determined via CellTiter-Glo proliferation assay. Downstream signaling was determined by phospho-flow analysis. Sanger sequencing was performed over theMYB-TYK2fusion gene to identify emergence of mutations. Site directed mutagenesis of theMYB-TYK2fusion construct was used to model an identified mutationin vitro. Computational modeling of theTYK2mutation and cerd docking was performed via ICM-Pro (Molsoft L.C.C.). The effect of long-term exposure to cerd on activation of JAK family kinases was investigated via western blot. A cerd resensitized line (cerdresen) was generated by culturing cerdres Ba/F3-MYB-TYK2cells in cerd free media for 5 weeks. Results Long-term exposure of Ba/F3-MYB-TYK2cells to cerd resulted in resistance with an 8.7-fold increase in IC50 compared to vehicle control cells (DMSO exposed) (IC50=6508 vs 739nM,p=0.001; Figure 1A). A novel mutation in the kinase domain ofTYK2(p.R987Q, c.3338G>A) was identified in ~50% of cerdres Ba/F3-MYB-TYK2cells. However,de novointroduction ofMYB-TYK2p.R987Q into parental Ba/F3 cells indicated that resistance to cerd was not due to the mutation alone, as these cells displayed no significant decreased sensitivity to cerd compared with control cells (IC50=1200 vs 739nM,p>0.05; Figure A). Computational modeling indicated the binding orientation of cerd to the mutated kinase domain was reversed 180º resulting in less favourable binding (TYK2p.R987Q vsTYK2, binding score= -18.6 vs -23.4). Phosphoflow analysis demonstrated increased JAK/STAT signalling in cerdres Ba/F3-MYB-TYK2compared with control cells (MFI= 35.2 vs 16.5,p=0.008) that persisted despite TYK2 kinase inhibition (MFI= 29.8 vs 2.3,p=0.004; Figure B). Expression of p.R987Q mutation did not result in increased pSTAT5 levels in Ba/F3-MYB-TYK2p.R987Q. Given that JAK2 heterodimerisation with other JAK proteins can lead to JAK/STAT activation and drug persistence (Meyeret al.2017), other kinases may facilitate phosphorylation of TYK2 in cerdres Ba/F3-MYB-TYK2.Western blot analysis confirmed a significant increase in TYK2 phosphorylation (p=0.01) and JAK1 expression (p=0.0008) in cerdres vs control Ba/F3-MYB-TYK2cells (Figure C). Cerd withdrawal resulted in potential resensitization of cerdres Ba/F3-MYB-TYK2to cerd with an associated decrease in IC50 (cerdres vs cerdresen, 6508 vs 2603nM,p=0.0003). However, IC50 levels did not decrease to levels observed in control cells (cerdresen vs control, 2603 vs 739nM, p=0.01), potentially due to increased activation of STAT5 from cerd-induced accumulation of pTYK2 (Tvorogovet al. 2018). Conclusions In vitromodeling suggests that persistent JAK/STAT activation is due to changes in TYK2 expression. Possible heterodimer formation with JAK1 in the setting of JAKi -cerd- exposure allows cells to become resistant. Consequently, the novel evidence of resistance mechanisms to JAKi, provide a rationale for the use of other small molecule inhibitors (e.g. HSP90i and HDACi), to potentially retain TYK2 degradation ability in resistant cells. This targeted approach may contribute to the treatment of patient withTYK2-rearranged ALL. Disclosures White: Bristol-Myers Squibb:Honoraria, Research Funding;Amgen:Honoraria.

scholarly journals Challenging Antimicrobial Susceptibility and Evolution of Resistance (OXA-681) during Treatment of a Long-Term Nosocomial Infection Caused by a Pseudomonas aeruginosa ST175 Clone

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Jorge Arca-Suárez ◽  
Pablo Fraile-Ribot ◽  
Juan Carlos Vázquez-Ucha ◽  
Gabriel Cabot ◽  
Marta Martínez-Guitián ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Nosocomial Infection ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
The Novel ◽  
Content Type ◽  
Narrow Spectrum ◽  
Extended Spectrum

ABSTRACT Selection of extended-spectrum mutations in narrow-spectrum oxacillinases (e.g., OXA-2 and OXA-10) is an emerging mechanism for development of in vivo resistance to ceftolozane-tazobactam and ceftazidime-avibactam in Pseudomonas aeruginosa. Detection of these challenging enzymes therefore seems essential to prevent clinical failure, but the complex phenotypic plasticity exhibited by this species may often lead to their underestimation. The underlying resistance mechanisms of two sequence type 175 (ST175) P. aeruginosa isolates showing multidrug-resistant phenotypes and recovered at early and late stages of a long-term nosocomial infection were evaluated. Whole-genome sequencing (WGS) was used to investigate resistance genomics, whereas molecular and biochemical methods were used for characterization of a novel extended-spectrum OXA-2 variant selected during therapy. The metallo-β-lactamase blaVIM-20 and the narrow-spectrum oxacillinase blaOXA-2 were present in both isolates, although they differed by an inactivating mutation in the mexB subunit, present only in the early isolate, and in a mutation in the blaOXA-2 β-lactamase, present only in the final isolate. The new OXA-2 variant, designated OXA-681, conferred elevated MICs of the novel cephalosporin–β-lactamase inhibitor combinations in a PAO1 background. Compared to OXA-2, kinetic parameters of the OXA-681 enzyme revealed a substantial increase in the hydrolysis of cephalosporins, including ceftolozane. We describe the emergence of the novel variant OXA-681 during treatment of a nosocomial infection caused by a Pseudomonas aeruginosa ST175 high-risk clone. The ability of OXA-681 to confer cross-resistance to ceftolozane-tazobactam and ceftazidime-avibactam together with the complex antimicrobial resistance profiles exhibited by the clinical strains harboring this new enzyme argue for maintaining active surveillance on emerging broad-spectrum resistance in P. aeruginosa.

Therapeutic Advances in Myeloproliferative Neoplasms: The Role of New-Small Molecule Inhibitors

2012 ◽  
pp. 406-410 ◽  
Author(s):  
Srdan Verstovsek
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Myeloproliferative Neoplasms ◽  
Janus Kinase ◽  
Treatment Focus ◽  
Rational Combination ◽  
Short And Long Term ◽  
Jak2 Inhibitors

Overview: The discovery that a somatic point mutation (JAK2V617F) in the Janus kinase 2 ( JAK2) is highly prevalent in patients with myeloproliferative neoplasms (MPNs) has been a crucial breakthrough in our understanding of the underlying molecular mechanisms of these diseases. Therefore, preclinical and clinical research in recent years has focused intensely on the development of new therapies targeted to JAK2. These efforts culminated in recent approval of ruxolitinib as the first official therapy for patients with intermediate- or high-risk myelofibrosis (MF). Therapy with JAK2 inhibitors substantially improves quality of life and reduces organomegaly in MF with or without JAKV617F mutation. Recent results suggest that patients with advanced MF may live longer when receiving therapy with ruxolitinib. However, JAK2 inhibitors do not eliminate the disease and new medications are needed to expand on the benefits seen with JAK2 inhibitors. Although many agents are still in the early stages of development, the wealth of publications and presentations has continued to support our growing understanding of the pathophysiology of MF as well as the potential short- and long-term outcomes of these new and diverse approaches to treatment. Focus of ongoing efforts is particularly on the improvements in anemia and fibrosis, as well as on rational combination trials of JAK2 inhibitors and other potentially active agents. Therapeutic potential and limitations of JAK2 inhibitors and other novel medications in clinical studies are reviewed.

scholarly journals Metabolic Effects of JAK1/2 Inhibition in Patients with Myeloproliferative Neoplasms

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Manali Sapre ◽  
Douglas Tremblay ◽  
Eric Wilck ◽  
Annie James ◽  
Amanda Leiter ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Mass Index ◽  
Adipose Tissue ◽  
Myeloproliferative Neoplasms ◽  
Janus Kinase ◽  
Metabolic Effects ◽  
Baseline Body Mass Index ◽  
Single Center ◽  
Baseline Weight

Abstract Ruxolitinib is an FDA approved janus kinase (JAK)1/2 inhibitor used to treat myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. We aimed to determine the metabolic consequences of ruxolitinib treatment in patients with MPNs. We performed a retrospective single-center cohort study utilizing an electronic medical record based database of patients who began treatment with ruxolitinib for MPNs from January 2010 to March 2017. We also examined the effects of ruxolitinib on adipose tissue JAK/STAT signaling in a mouse model. 127 patients were identified, of which 69 had data available for weight, and at least one other parameter of interest before, and 72 weeks after starting ruxolitinib. Mean baseline weight was 73.9 ± 17.0 kg, and 78.54 ± 19.1 kg at 72 weeks (p < 0.001). 50% of patients gained >5% body weight. Baseline body mass index (BMI) was 25.8 ± 4.8 kg/m2, and 27.5 ± 5.5 kg/m2 at 72 weeks (p < 0.001). Patients treated with ruxolitinib had a higher systolic blood pressure, serum AST, and ALT at 72 weeks, compared with baseline (p = 0.03, p = 0.01, p = 0.04, respectively). In mice, ruxolitinib decreased basal and GH-stimulated STAT5 phosphorylation in adipose tissue. As pharmacological JAK1/2 inhibitors are being developed and used in clinical practice, it is important to understand their long-term metabolic consequences.

scholarly journals Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 988-992 ◽  
Author(s):  
Stephen T. Oh ◽  
Erin F. Simonds ◽  
Carol Jones ◽  
Matthew B. Hale ◽  
Yury Goltsev ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Adaptor Protein ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Negative Feedback Regulation ◽  
Base Pair Deletion ◽  
Stat Signaling

Abstract Dysregulated Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F–negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34+ early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis.

scholarly journals Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Daniele Cattaneo ◽  
Alessandra Iurlo
Keyword(s):  
Signaling Pathway ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Infectious Complications ◽  
Janus Kinase ◽  
Dramatic Improvement ◽  
Loss Of Function ◽  
Jak Inhibitors ◽  
Increased Risk ◽  
Stat Signaling

BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.

scholarly journals Genetic Resistance to JAK2 Enzymatic Inhibitors Is Overcome by HSP90 Inhibition

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 62-62
Author(s):  
Oliver Weigert ◽  
Andrew A. Lane ◽  
Liat Bird ◽  
Nadja Kopp ◽  
Angela V Toms ◽  
...  
Keyword(s):  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Jak2 V617f ◽  
Kinase Domain ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Resistance Mutations ◽  
Hsp90 Inhibitors ◽  
Imatinib Resistance

Abstract Abstract 62 Mutation within the kinase domain of tyrosine kinases is a common mechanisms of resistance to enzymatic inhibitors. Inhibitors of janus kinase 2 (JAK2) are under evaluation in patients with myeloproliferative neoplasms (MPNs), B-cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit CRLF2, and other tumors with constitutive JAK2 signaling. To identify resistance mutations in JAK2, we randomly mutagenized human JAK2 R683G, which is observed in approximately half of CRLF2-rearranged B-ALL. We transduced the mutagenized JAK2 cDNA library into murine Ba/F3 cells that express CRLF2. Expression of CRLF2 and JAK2 R683G confers IL3 independent growth in Ba/F3 cells. The transduced population was selected in the JAK2-selective inhibitor NVP-BVB808 in the absence of IL3. Multiple BVB808-resistant clones were recovered that harbored either E864K, Y931C or G935R mutations in JAK2. Alignment of homologous regions of the JAK2 kinase domain (JH1) with ABL1 demonstrated that the three mutations are located in regions homologous to imatinib resistance hotspots in ABL1. Codons Y931 and G935 are within the hinge region of the kinase domain. Based on structural modeling, Y931C is likely to inhibit substrate binding. E864K is located in the middle of b3 following the P-loop in the N-lobe and may modify the structure and flexibility of the preceding P-loop, thus destabilizing the conformation required for inhibitor binding. We expressed JAK2 V617F alleles harboring Y931C, G935R or E864K in Ba/F3-EPOR cells and exposed the cells to the JAK2 enzymatic inhibitors JAK inhibitor-1, NVP-BSK805, TG101348, tofacitinib (formerly tasocitnib), ruxolitinib (formerly INCB18424) and BVB808. All three mutations conferred 2- to >10-fold resistance against BVB808, NVP-BSK805, TG101348, ruxolitinib and JAK inhibitor-1. Y931C and E864K but not G935R conferred resistance to tofactinib. Modeling of G935R indicated that a 935R side-chain would occlude the hydrophobic channel of the ATP-binding pocket. As a consequence, this mutation would decrease the binding affinity of compounds occupying the hydrophobic channel like JAK inhibitor-1 or BSK805, but not affect the potency of tofactinib, which does not bind in this region. Mutation of G935 to arginine, histidine or glutamine reduced the inhibitory effects of JAK inhibitor-1, but not tofacitinib, on JAK2 kinase domain activity. None of the codon 935 mutations had significant effects on Km or Vmaxin vitro. BVB808 treatment partially reduced activation state-specific phosphorylation of STAT5 in Ba/F3-EPOR/JAK2 V617F cells but not in Ba/F3-EPOR/JAK2 V617F/G935R or G935H cells. JAK2 is a known client of HSP90, and HSP90 inhibitors promote the degradation of both wild-type and mutant JAK2. We hypothesized that resistance mutations within the JAK2 kinase domain would not affect JAK2 degradation induced by HSP90 inhibitors. We assayed the cytotoxicity of the resorcinylic isoxazole amide NVP-AUY922 and the benzoquinone ansamycin 17-AAG in Ba/F3 cells that express the erythropoietin receptor (EPOR) and JAK2 V617F, which is observed in more than half of MPNs. Mutation of JAK2 V617F to include E864K, Y931C or G935R did not affect sensitivity to either AUY922 or 17-AAG. In fact, AUY922 was more active against cells harboring G935R (GI50, 3.87 nM) or E864K (GI50, 6.14 nM) compared to cells with no resistance mutation (GI50, 14.7 nM; p<0.05). Both HSP90 inhibitors had similar potency in Ba/F3-CRLF2 cells expressing the resistance mutations in cis with R683G. Treatment of both lines with AUY922 at levels achievable in vivo reduced P-JAK2, P-STAT5, and total JAK2 regardless of mutations that conferred resistance to enzymatic JAK2 inhibitors. Thus, HSP90 inhibitors maintain activity in JAK2-dependent cells with resistance mutations in JAK2. Treatment of JAK2-dependent cancers with HSP90 inhibitors is an attractive treatment strategy either up-front or upon the selection of resistance to JAK2 enzymatic inhibitors. Disclosures: Gaul: Novartis: Employment. Vangrevelinghe:Novartis: Employment. De Pover:Novartis: Employment. Regnier:Novartis: Employment. Erdmann:Novartis: Employment. Hofmann:Novartis: Employment. Eck:Novartis: Consultancy, Research Funding. Kung:Novartis Pharmaceuticals: Consultancy, Research Funding. Radimerski:Novartis Pharma AG: Employment. Weinstock:Novartis: Consultancy, Research Funding.

New insights into the structure and function of the pseudokinase domain in JAK2

2013 ◽  
Vol 41 (4) ◽  
pp. 1002-1007 ◽  
Author(s):  
Olli Silvennoinen ◽  
Daniela Ungureanu ◽  
Yashavanthi Niranjan ◽  
Henrik Hammaren ◽  
Rajintha Bandaranayake ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Critical Role ◽  
Kinase Domain ◽  
Janus Kinase ◽  
Regulatory Function ◽  
Tyrosine Kinase Domain ◽  
Polycythaemia Vera ◽  
Underlying Mechanisms ◽  
Dynamics Simulations ◽  
High Level

JAK (Janus kinase) 2 plays a critical role in signal transduction through several cytokine receptors. JAKs contain a typical tyrosine kinase domain preceded by a pseudokinase [JH2 (JAK homology 2)] domain which has been considered to be catalytically inactive. Identification of activating mutations in the JH2 domain of JAK2 as the major cause for polycythaemia vera and other MPNs (myeloproliferative neoplasms) demonstrate the critical regulatory function for this domain, but the underlying mechanisms have remained elusive. We have performed biochemical and functional analysis on the JH2 domain of JAK2. The results indicate that JH2 functions as an active protein kinase and phosphorylates two residues in JAK2 (Ser523 and Tyr570) that have been shown previously to be negative regulatory sites for JAK2 activity. The crystal structure of the JAK2 JH2 domain provides an explanation for the functional findings and shows that JH2 adopts a prototypical kinase fold, but binds MgATP through a non-canonical mode. The structure of the most prevalent pathogenic JH2 mutation V617F shows a high level of similarity to wild-type JH2. The most notable structural deviation is observed in the N-lobe αC-helix. The structural and biochemical data together with MD (molecular dynamics) simulations show that the V617F mutation rigidifies the αC-helix, which results in hyperactivation of the JH1 domain through an as yet unidentified mechanism. These results provide structural and functional insights into the normal and pathogenic function of the JH2 domain of JAK2.

scholarly journals Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms

2018 ◽  
Vol 10 (436) ◽  
pp. eaan8292 ◽  
Author(s):  
Ofir Wolach ◽  
Rob S. Sellar ◽  
Kimberly Martinod ◽  
Deya Cherpokova ◽  
Marie McConkey ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Neutrophil Function ◽  
Janus Kinase ◽  
Neutrophil Extracellular Trap ◽  
Jak2 Inhibitor ◽  
Stat Signaling ◽  
Extracellular Trap ◽  
Deep Vein

Thrombosis is a major cause of morbidity and mortality in Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), clonal disorders of hematopoiesis characterized by activated Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. Neutrophil extracellular trap (NET) formation, a component of innate immunity, has been linked to thrombosis. We demonstrate that neutrophils from patients with MPNs are primed for NET formation, an effect blunted by pharmacological inhibition of JAK signaling. Mice with conditional knock-in of Jak2V617F, the most common molecular driver of MPN, have an increased propensity for NET formation and thrombosis. Inhibition of JAK-STAT signaling with the clinically available JAK2 inhibitor ruxolitinib abrogated NET formation and reduced thrombosis in a deep vein stenosis murine model. We further show that expression of PAD4, a protein required for NET formation, is increased in JAK2V617F-expressing neutrophils and that PAD4 is required for Jak2V617F-driven NET formation and thrombosis in vivo. Finally, in a population study of more than 10,000 individuals without a known myeloid disorder, JAK2V617F-positive clonal hematopoiesis was associated with an increased incidence of thrombosis. In aggregate, our results link JAK2V617F expression to NET formation and thrombosis and suggest that JAK2 inhibition may reduce thrombosis in MPNs through cell-intrinsic effects on neutrophil function.

scholarly journals Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2592
Author(s):  
Steven De Almeida ◽  
Mathilde Regimbeau ◽  
Gaëtan Jego ◽  
Carmen Garrido ◽  
François Girodon ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Targets ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Stat3 Phosphorylation ◽  
Stat Signaling ◽  
Shock Proteins

Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.

scholarly journals Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

2012 ◽  
Vol 209 (2) ◽  
pp. 259-273 ◽  
Author(s):  
Oliver Weigert ◽  
Andrew A. Lane ◽  
Liat Bird ◽  
Nadja Kopp ◽  
Bjoern Chapuy ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Genetic Resistance ◽  
Heat Shock Protein 90 ◽  
Jak2 V617f ◽  
Kinase Domain ◽  
Hsp90 Inhibitor ◽  
Janus Kinase ◽  
Cytokine Receptor ◽  
Hsp90 Inhibition

Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor–like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100–1,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.

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