JAK/STAT signaling pathway inhibitors for leukemia therapeutic potential : a systematic review on in vitro literatures

doi:10.21203/rs.3.rs-4813515/v1

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Research Article

JAK/STAT signaling pathway inhibitors for leukemia therapeutic potential : a systematic review on in vitro literatures

https://doi.org/10.21203/rs.3.rs-4813515/v1

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Background

Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs) is a main signaling pathway in the immune system, autoimmune disease and in many malignancies such as leukemia. Limiting this signaling pathway has so far been investigated in the treatment of some diseases such as lymphoma, and in this systematic review, we will investigate the role of this type in leukemia.

Method

This systematic review was written based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria and the principle of non-bias was respected. All the articles from 2014–2024 were extracted from Web of Science, PubMed and Scopus databases. We extracted the extracting inhibitors, related immunity elements, JAK/STAT kind, side signaling pathway.

Results

Three authors searched the database, after screening full texts, 17 articles were included. 15 inhibitory drugs for the JAK/STAT pathway were extracted in studies, which inhibit this signaling pathway in vitro and in cultured human leukemic cells. The most signaling pathways in leukemia were limited to STAT 5 and STAT 3, which were inhibited by Thymoquinone, Ritanserin, Dactocilib and Ruxolitinib. On the other hand, leukemic cells act exclusively through the JAK 2 pathway, which was specifically inhibited by Ruxolitinib and AG490. Increased apoptosis of leukemic cells and decreased cell survival was the result of monotherapy and multitherapy of these inhibitors in the studies available to us.

Conclusion

Inhibition of JAK/STAT pathway is associated with the reduction of leukemic cell growth and apoptosis of these types of cells, which seems to be a great therapeutic potential for clinical studies in all types of leukemia. We suggest that future studies investigate this type of treatment especially in children and evaluate our results.

Systematic review

Janus kinases

signaling pathway

inhibitors

Janus kinase (JAK) is a signal transducer and transcription activator of an intracellular communication pathway responsible for cell proliferation, differentiation, apoptosis, and immune regulating factor including inflammation, tissue repair and autoimmune regulation(1–3). Janus kinase family with four isoforms as JAK1, JAK2, JAK3, and TYK2 are known as signaling mediators of other proteins such as signal transducer and activator of transcription (STAT)(4, 5). Affecting JAKs, Cytokines triggered by phosphorylating STATs, transfer their effect to STATs. In mammals, the STATS is expressed as 7 proteins including STAT1-4, STAT5A, STAT5B, and STAT 6 from the same family, where each interleukin applies its instructions by phosphorylation of a spectrum of those 7 proteins(6, 7). Necrosis factors stimulate this signaling pathway, each of which uses JAK members, influences a range of STATs to regulate T lymphocytes, gamma interferon (INF- γ), natural killer (NK) cells, and inflammatory effects of the immune system(1, 6, 8). The property of JAK/STAT signaling among a wide range of inflammatory and necrotic factors has played an important role in the pathology of various types of cancer for this family.

Attempts to prevent the signaling of this pathway have been introduced as a therapeutic approach with high potential. JAK2 and STATs 1, 3, and 5 play an essential role in the growth and signaling of leukemia(9, 10). The activity of this signaling pathway ultimately increases the growth and differentiation of leukemic cells and malignant stem cells and protects them against the body's natural apoptosis(11, 12). Many chemotherapy drugs that are specially focused on the signaling pathway of leukemia cells, such as T-cell acute lymphoblastic leukemia (T-ALL) and K652, have severely limited the growth of malignant leukemia and lymphoma cells(13, 14). One of the most important of this drug is is ruxolitinib, which targets STAT1,3,5 and JAK2 and 3 and blocks the BCR-ABL1 signaling pathway(15).

Unfortunately, this treatment method is still being pursued in the experimental stage and not clinically, although it should be noted that many inhibitors have been introduced, each of which specifically affects a certain range of pathways. A systematic study that can compare these inhibitors side by side and evaluate the specialized path of each one may be the key to entering this type of therapy into leukemia treatment choices in children and adults. In this systematic study, we are looking for an answer to the research question raised about the possibility of treating leukemia with JAK/STAT signaling pathway inhibitors.

o Protocol and registration

This systematic study was written based on the accepted criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and in order to comply with the principle of non-bias, we used the Cochrane Manual for Systematic Reviewers 5.1.0 for clinical studies and reviewed the studies in terms of allocation concealment, blinding of participants, study personnel and outcome assessors. The research question of this systematic study was based on PICO criteria (Patient/Population, Intervention, Comparison, Outcomes).

o Eligibility criteria and search strategy

We assessed published studies from January-2014 to 2024 in databases such as Web of Science, PubMed and Scopus. The definition of leukemia was considered based on ICD-11, that all studies that investigated leukemia based on the above definition were reviewed. Studies that directly investigated JAK/STAT signaling were included in the study. Studies with following characters were eliminated:

• Studies that were not open access were selected based on the PRISMA checklist if the abstract was complete, and the corresponding author was contacted for the results if more information was needed. Studies whose abstract structure was not complete based on this criterion were excluded from the review

Non-English studies were completely excluded.
studies that based on cultured cell did not extract from human
Our research question was based on the treatment of Leukemia, so studies that investigated the therapeutic effect of a specific drugs were not JAK/STAT inhibitors were excluded, also studies that investigated second non-inhibitor effect on an inhibitor drug eliminated too. This for concentrate on inhibitors process.

The studies were arranged according to a timeline, older similar studies were replaced by new studies.

We assessed published studies from January-2014 to 2024 in databases such as Web of Science, PubMed and Scopus. We examined our own title in the Cochrane Data Base to find similarities and review similar systematic studies. We obtained our keywords by searching in the Mesh database. Two groups of two persons searched the database (first Web of Science, then PubMed and Scopus) separately according to the keywords JAK/STAT inhibitors, leukemia (AML, ALL, CLL and CML). According to the PRISMA criteria, similar and non-English items were first removed, and then both groups screened titles and abstracts. The articles that were eligible to be included were provided to the co-author, so that the studies would be aggregated. In case of non-subscription, the articles were reviewed under the supervision of the first author and the problem was resolved. Finally, 20 studies were selected and all their texts were assessed, there was no any article that included by manual citation search.

o Data extraction, Study selection and methodological quality assessment

The correspond and first author formed the summary table and reviewed the studies based on the Cochrane tool on risk of bias 2 (Rob 2) (16) To extract the data, a group of three authors, started extracting inhibitors, related immunity elements, JAK/STAT kind, side signaling pathway from the articles separately and without communication, the results were under the supervision of the correspond and first author and all the articles were categorized based on the report of the leukemia types, results were reviewed under the supervision of the first and co-respond author based on the Cochrane guidelines to minimize the bias error and ensure the accuracy of the information.

• Study process

A team of two authors searched the keywords mentioned in the method in web of science, PubMed and Scopus databases respectively. A total of 1580 studies were obtained from all three databases. Both of them removed the comments from the congress, Review, letter to the editor. 867 studies remained, which this two-person team screened titles and abstracts, and non-English and non-free studies that were unstructured or contained incomplete information about the method. they also removed similar titles. 391 studies were left and we studied their summary, the criterion for removing articles at this stage was the basic criteria in our research question, of which 148 studies had the necessary eligibility. Aa well as the studies that investigated the interaction of drugs on the inhibitors were excluded. 26 studies remained and their full text was studied. After a complete study, 20 articles were given to the first and co-authors, and after checking the risk of bias by RoB 2 for in vivo and ex vivo, 17 studies were considered for conclusion (Diagram 1).

All the studies included the culture of human cells in vitro and then evaluation and verification in vivo. Only one clinical study was conducted(17), which due to the lack of free access and of course the lack of cooperation of the responsible author, it is possible to measure the risk of complete bias. It was not, so it was removed.

Inhibitors target all type of leukemia

Treatment based on this inhibition of the JAK/STAT pathway in myeloid leukemias is a more likely choice than the lymphoid type. 41% of our available studies investigated this type of treatment in AML (Acute myeloid leukemia) and 29% in CML (Chronic myeloid leukemia), and the rest of the studies were Lymphoid leukemias arrived( supplementary 1 ).

Figure 1 has categorized the inhibitors of each type of leukemia, based on our studies, some drugs have the ability to limit the JAK/STAT pathway in each type of leukemia. Roxilitinib is a good example of a broad-spectrum drug in leukemia that is both a STAT and JAK inhibitor. On the other hand, some drugs were mentioned only in AML by the articles, which we can mention Ritanserin and Anlotinib, which were used more specifically for acute lymphoid leukemia.Similarities in CML and AML inhibitors can be observed in studies, and it is possible to limit the JAK/STAT pathway in both types with Fedratinib and Thymoquinone, if these similarities are not observed between ALL(Acute lymphoblastic leukemia) and CLL(Chronic lymphoblastic leukemia).

What was evident in our available studies, JAK/STAT inhibitors have the ability to limit the progress of malignant cells in leukemia, the diversity of these inhibitors gives us a suitable choice for each type of leukemia specifically.

JAK/STAT inhibitors induced cell apoptosis and limit leukemic cell signaling

Figure 2 shows in detail the target pathway of each of the obtained inhibitors.

JAK/STAT inhibitors in ALL

Types of T cells in the course of ALL that have become malignant are called Early T-cell precursor and T-ALL, which show high levels of phosphorylated STAT 1, STAT 3 and STAT 5 in the course of ALL. they give. As a cytokine secreted by many cells, especially T cells, IL-17 activates the signaling pathways of T cells, including ETP-ALL((Early T cell Progenitor Acute Lymphoblastic Leukemia) and T-ALL (13, 18), after the expression of this cytokine, the level of JAK-STAT5 pathway is phosphorylated. PI3K-AKT-mTOR and MEKERK are increased in T-ALL of the phosphorylated STAT 5 pathway in ETP-ALL. Treatment of ALL cells from affected children with BEZ-235 and ruxolitinib inhibits this increase in the phosphorylated level of STAT 5 and prevents the growth of ALL cells and their further differentiation. Also, ruxolitinib as a JAK inhibitor reduced the phosphorylated level of STATs 1, 3 and 5 in mice.

JAK/STAT inhibitors in AML

The involvement of cytokines in AML is also evident, pro-inflammatory cytokines such as IL-8, IL-1β, IL-6, and IL-10 in AML with increased signaling and expression of STAT3, STAT5 pathways, as well as JAK 1 and 2 kinases in the cell. is the primary leukemia(19), also IL-1β increases the expression of JAK 2 in these cells, ruxolitinib and fedratinib(20, 21), as well as specialized JAK inhibitors such as solcitinib (JAK2), momelotinib (JAK1/2), and tofacitinib (JAK3), phosphorylate the STAT pathway They inhibit them in bone marrow cells and also control and reduce JAK 2 signaling level in bone marrow stem cells of leukemia patients.

Cheng-Jin Ai observed in his measurement that IL-6 activates the JAK1/STAT3 pathway and not p-JAK1, p-STAT3, that Gossypol acetic acid inhibits the effect of IL-6 on the JAK1/STAT3 pathway(22). It neutralizes the self-renewal of leukemia cells. This was in contrast to the phosphorylation pathway that was inhibited by Ruxolitinib. Contrary to this study, ritanserin reduces the brightness of phosphorylated JAK1, JAK3, STAT3, STAT5, MEK1/2 in Kasumi-1 and KG-1α cells(23), it is worth mentioning in this study that the reduction of apoptosis of AML cells and the increase of JAK1 and the level of unphosphorylated STAT3, STAT5 in combination with RO8191. This compound is considered an interferon agonist that induces phosphorylated STAT 1, 3, 5 and 6 pathways as a pro-inflammatory factor. In fact, in the combination treatment of ritanserin with RO8191, in addition to reducing the ability of ritanserin to limit JAK/STAT, other signaling pathways will intensify in the development of malignancy. sodium metaarsenite (KML001) and anlotinib decrease the level of phosphorylated STAT1, STAT3 and STAT5 in Leukemia stem cells (LSCs) (14, 21).

Al-Rawashde showed in comprehensive research that Thymoquinone, as a high penetration inhibitor in leukemia, has the ability to limit STAT3, STAT5a, and STAT5b(24). In this research, JAK2 was severely decreased in MV4-11 cells, this group of cells in bone marrow affected by leukemia is considered as a marker of myeloid leukemia. What is noteworthy is that Thymoquinone also reduced the non-phosphorylated level of these pathways, although it should be noted that this inhibitor can also be used in CML.

JAK/STAT inhibitors in CML

Thymoquinone increases the apoptosis of CML cells and limits the growth of damaged cells, also this time in K562 cells it reduces the levels of STAT 3 and 5 in addition to JAK 2(24). The difference in the function of this inhibitor is in the target cell in AML and CML, which, of course, K562 cells are the target cells of other inhibitors such as Imatinib, Fedratinib and Dehydrocostus lactone to limit JAK 2(25, 26).

Fedratinib limits the proliferation of K562 cells and shows a noticeable decrease in the level of phosphorylated STAT 5(27). These types of cells are recognized as the first cell line in CLL and thus have a diagnostic value for this type of leukemia, which of course are enhanced with HS-5 stem cells. The presence of HS-5 in the culture medium of K562 does not allow the treatment with Fedratinib and imatinib, as inhibition of STAT and kinases in the presence of this type of stem cells cannot be done by inhibitors. This topic alone has the potential for further research that restricting some stem cells in one of the sources of stem cells, namely the bone marrow, may be able to prevent the growth of malignant cells. Dehydrocostus lactone decreases both p-STAT3, p-STAT5 and p-JAK2 levels in K562 cells, since JAK 2 is considered an important signaling pathway in bone marrow cells in CML(25), an important therapeutic pathway will form by Dehydrocostus lactone.

The combination of several inhibitors gives the ability to cover more signaling pathways than monotherapy, the combination of ruxolitinib and nilotinib(28), in addition to reducing the level of p-STAT5 and JAK2, also controls and limits the transplantable leukemogenic activity of CML CD34+. Imatinib alone was able to limit phosphorylation of JAK2, JAK3, and STAT3, but combination with JAK inhibitors such as ruxolitinib and tofacitinib provides a treatment that does not affect JAK2/3, or STAT3/5 phosphorylation(26, 29).

JAK/STAT inhibitors in CLL

By activating the signaling pathway, pro-inflammatory cytokines reduce the body's natural apoptosis for malignant cells and increase survival in tuberculosis. IL-4 and IL-6 elevate the expression of STAT3 or STAT6 pathways(19), CLL enables the growth and differentiation of leukemic cells, and cerdulatinib inhibits the phosphorylation of JAK1, JAK3 and STAT6 in the IL-4 pathway and JAK1, JAK2 and STAT3 in the IL-6 pathway, and induce cell apoptosis(30). Ailin Guo was able to prevent the proliferation of leukemia cells that showed resistance to ibrutinib with cerdulatinib, this point will be important from the point of view that the inhibitors will not transfer resistance. If several inhibitors are used as multitherapy, or if there is no response to monotherapy and another inhibitor is selected, a complete response can be expected from the treatment. As we see an increase in CLL cell death rate up to 50% in the combination of ibrutinib and AG490, choosing combined treatments will be preferable over monotherapies(31).

In our study we show that the main signaling pathway of leukemia passes through STAT 1, STAT 3 and STAT 5, and these three pathways proceed with the comprehensive cooperation of JAK 2 and JAK 3, for this reason, JAK inhibitor drugs play a significant role in preventing the signaling of leukemia indicator cells such as K652 and leukemia stem cells. they do. We have categorized and introduced chemotherapeutic drugs that are capable of preventing the growth and differentiation of leukemic cell culture by the available studies, these inhibitors had the potential to cause cell death and reduce survival in the laboratory. These drugs also limit the signaling pathway of pro-inflammatory cytokines which are effective in reducing the apoptosis of malignant bone marrow cells, the result of this type of therapy is ultimately both the reduction of the growth and differentiation of malignant cells and their apoptosis. leukemia can be managed and controlled by interfering with the regulatory pathways of immune system cytokines and exclusively in the present study the JAK/STAT signaling pathway inhibitors. leukemia signaling through in STAT 1, 3,5 and JAK2 and JAK3 is necessary to increase the ratio of Th1/Th17(T helpers) and decrease T-ALL(32, 33), the STAT 1 pathway order to differentiate CD4 + from Th1; it indicates the path of influence of these cytokines in leukemia and the focal point for disrupting this cycle by inhibitors such as ruxolitinib or ritanserin and prevention of bone marrow (BM) inflammation as well as hematopoietic BM pancytopenia.

Zeidan was the author of the only clinical study available to us, which performed monotherapy and oral multitherapy of INCB052793 and itacitinib and azacitidine for AML and MDS(Myelodysplastic syndrome) in two phases(17), none of which produced adequate response. But ruxolitinib was able to produce an active response in 25 percent of lymphoma cells, which Moskowitz calls a precise treatment approach(34). Ruxolitinib also breaks the resistance of T-ALL to dexamethasone-induced apoptosis, which is considered a positive treatment point for resistant hemophagocytic lymph histiocytosis(19, 35). Recognize the different inhibitors and the target signal path of each one in leukemia makes it possible to choose monotherapy or multitherapy, as well as the precise selection of the inhibitor.

Our studies showed that the multitherapy of Ruxolitinib and fedratinib and Imatinib, Tofacitinib and Ruxolitinib by limiting the JAK 2 pathway and preventing signaling in STAT 1, 3 and 5, which in addition to K652 and T-ALL cell death, prevents the expression of leukemic genes in these cells. and adjacent cells(35, 36). As our results showed, malignant cells with JAK-STAT pathway use bone marrow stem cells as support in addition to transferring genes such as BCR-ABL1(37). This is the natural and programmed property of cells to escape from apoptosis induced by the immune system in leukemic cells with the involvement of IL-6, IL-8 and tumor necrosis factor (TNF-a) cytokines in leukemic cells repeatedly and with the help of JAK/STAT is done the need for chemotherapy that(19, 38). In addition to the apoptosis of malignant cells, blocks the progression of the remaining cells, can be achieved with inhibitors of kinases and STATs. Other signaling pathways also need to be identified so that a comprehensive multitherapy can create a high therapeutic synergism, and this will reduce the need for invasive treatments such as bone marrow transplantation or other stem cells to some extent. It should be noted that the problems of these invasive methods, such as finding a donor or rejecting a transplant, are not related to signaling pathway inhibitors(39–41). Another problem we encountered in the results is the possibility of leukemic cells backing up from the bone marrow stem tissue, which may be the reason for the recurrence of the disease, especially in children, which our results proved by limiting the signaling pathway can be avoided.

It has been proven that acquired leukemia is marked by a proinflammatory state whereby activated Th1 along with the CD8 + T cells and associated proteins lead to cellular damage,(42, 43) within which the level of regulatory T lymphocytes (Tregs) changes(44). The malignant results in the dysfunction of a specific type of Tregs, CD4 + CD25 + Foxp3 + in patients with leukemia, which can subsequently suppress the effects of natural effector T cells and the IFN-γ production(45, 46). leukemia signaling through STAT 1, 3 and 5 is necessary to increase the ratio of Th1/Th17 and decrease Treg, it is precisely seen in IL-6 and IL-17 signaling along with STAT3 and STAT5 and for every type of leukemia, the JAK2 pathway(22, 45). Our inhibitors by limiting involvement of IL-17 and IL-6, reduce the signaling level of these cytokines in the JAK/STAT pathway and prevent the survival of leukemic cells. In fact, specific inhibitors of the JAK/STAT pathway are not broad-spectrum immunosuppressors, but they specifically regulate the disorder of T lymphocytes to prevent the progression of malignancy.

In summary, focusing on signaling pathways as an alternative for the treatment of inflammation and BM malignant such as leukemia, would be easier to use, accessible and tolerable for patients. Additionally, the need for invasive interventions is eliminated by regulating cytokines, and the treatment procedure is more acceptable to the patients. Concentrating on the components of the immune system, the balance of cytokines and immune mediators brings about the idea that the type of treatment via regulation of inflammatory factors in autoimmune diseases, i.e. immune system cytokines, it can bring appropriate and reliable responses. Controlling inflammation and BM destruction by focusing on the signaling pathway of JAK/STAT, either as an independent therapeutic pathway or in combination with current treatments, in order to reduce the relapse rate and increase the response rate of treatment will be a suitable option for patients.

Based on the studies we obtained, there is a possibility of treatment based on inhibiting the JAK/STAT pathway in leukemia, and pharmacological studies have introduced specialized chemical compounds for each member of this pathway. Our studies showed that these inhibitors effectively limit human leukemic cells, especially cells extracted from children, and increase cell apoptosis. Based on our results, the inhibition of JAK/STAT signaling pathway will be a therapeutic choice for leukemia, which of course requires clinical studies to prove this issue well. In this study, we collected all the inhibitors from the studies and examined their role, we hope these results will be useful for future studies.

Ethics approval and consent to participate

All procedures performed in this systematic review involving human participants studies, were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The present study is a research project that held under nephrology department of Hormozgan university medical science supervision.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare no competing interests.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors' contributions

M.S and Z.K are the supervisor and make summarized table. S.Z.S. and M.A.B searched through data bases, S.Z.S., M.S and A.A.F. extracted data. Z.K., M.A.B and M.S wrote the manuscript. All authors checked and read the final passage.

Acknowledgment

We would like to thank the Department of hematology at Bandar Abbas University of Medical Sciences for their assistance in this study and for their efforts in verifying our results.

Meyer LK, Verbist KC, Albeituni S, Scull BP, Bassett RC, Stroh AN, et al. JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation. Blood. 2020;136(6):657-68.
Ruganzu JB, Zheng Q, Wu X, He Y, Peng X, Jin H, et al. TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway. Exp Neurol. 2021;336:113506.
Di Benedetto P, Ruscitti P, Berardicurti O, Panzera N, Grazia N, Di Vito Nolfi M, et al. Blocking Jak/STAT signalling using tofacitinib inhibits angiogenesis in experimental arthritis. Arthritis Res Ther. 2021;23(1):213.
Morris R, Kershaw NJ, Babon JJ. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 2018;27(12):1984-2009.
Chen D, Liu Y, Chen J, Lin H, Guo H, Wu Y, et al. JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes. Eur J Pharmacol. 2021;902:174121.
Nan Y, Wu C, Zhang YJ. Interferon Independent Non-Canonical STAT Activation and Virus Induced Inflammation. Viruses. 2018;10(4).
Hammarén HM, Virtanen AT, Raivola J, Silvennoinen O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine. 2019;118:48-63.
Zhan RZ, Rao L, Chen Z, Strash N, Bursac N. Loss of sarcomeric proteins via upregulation of JAK/STAT signaling underlies interferon-γ-induced contractile deficit in engineered human myocardium. Acta Biomater. 2021;126:144-53.
Fasouli ES, Katsantoni E. JAK-STAT in Early Hematopoiesis and Leukemia. Front Cell Dev Biol. 2021;9:669363.
Waldmann TA. JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics. Mol Cell Endocrinol. 2017;451:66-70.
McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Bäsecke J, et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia. 2008;22(4):708-22.
Liang D, Wang Q, Zhang W, Tang H, Song C, Yan Z, et al. JAK/STAT in leukemia: a clinical update. Mol Cancer. 2024;23(1):25.
Kuzilková D, Bugarin C, Rejlova K, Schulz AR, Mei HE, Paganin M, et al. Either IL-7 activation of JAK-STAT or BEZ inhibition of PI3K-AKT-mTOR pathways dominates the single-cell phosphosignature of ex vivo treated pediatric T-cell acute lymphoblastic leukemia cells. Haematologica. 2022;107(6):1293-310.
Yoon JS, Kim ES, Park BB, Choi JH, Won YW, Kim S, Lee YY. Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside. Int J Oncol. 2015;46(5):1953-62.
Habbel J, Arnold L, Chen Y, Möllmann M, Bruderek K, Brandau S, et al. Inflammation-driven activation of JAK/STAT signaling reversibly accelerates acute myeloid leukemia in vitro. Blood Adv. 2020;4(13):3000-10.
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
Zeidan AM, Cook RJ, Bordoni R, Berenson JR, Edenfield WJ, Mohan S, et al. A Phase 1/2 Study of the Oral Janus Kinase 1 Inhibitors INCB052793 and Itacitinib Alone or in Combination With Standard Therapies for Advanced Hematologic Malignancies. Clin Lymphoma Myeloma Leuk. 2022;22(7):523-34.
Maude SL, Dolai S, Delgado-Martin C, Vincent T, Robbins A, Selvanathan A, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125(11):1759-67.
Spaner DE, Luo TY, Wang G, Schreiber G, Harari D, Shi Y. Paradoxical activation of chronic lymphocytic leukemia cells by ruxolitinib in vitro and in vivo. Front Oncol. 2023;13:1043694.
Beckman JD, DaSilva A, Aronovich E, Nguyen A, Nguyen J, Hargis G, et al. JAK-STAT inhibition reduces endothelial prothrombotic activation and leukocyte-endothelial proadhesive interactions. J Thromb Haemost. 2023;21(5):1366-80.
Jiang Y, Liu L, Jiang Y, Li Z, Feng L, Zhuang X, et al. Preclinical Evaluation of the Multiple Tyrosine Kinases Inhibitor Anlotinib in Leukemia Stem Cells. Pharmaceuticals (Basel). 2022;15(11).
Ai CJ, Chen LJ, Guo LX, Wang YP, Zhao ZY. Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction. World J Stem Cells. 2024;16(4):444-58.
Tan J, Zhong M, Hu Y, Pan G, Yao J, Tang Y, et al. Ritanserin suppresses acute myeloid leukemia by inhibiting DGKα to downregulate phospholipase D and the Jak-Stat/MAPK pathway. Discov Oncol. 2023;14(1):118.
Al-Rawashde FA, Al-Wajeeh AS, Vishkaei MN, Saad HKM, Johan MF, Taib WRW, et al. Thymoquinone Inhibits JAK/STAT and PI3K/Akt/ mTOR Signaling Pathways in MV4-11 and K562 Myeloid Leukemia Cells. Pharmaceuticals (Basel). 2022;15(9).
Cai H, Qin X, Yang C. Dehydrocostus Lactone Suppresses Proliferation of Human Chronic Myeloid Leukemia Cells Through Bcr/Abl-JAK/STAT Signaling Pathways. J Cell Biochem. 2017;118(10):3381-90.
Yagi K, Shimada A, Sendo T. Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia. Eur J Pharmacol. 2018;825:28-33.
Okabe S, Tauchi T, Katagiri S, Tanaka Y, Ohyashiki K. Combination of the ABL kinase inhibitor imatinib with the Janus kinase 2 inhibitor TG101348 for targeting residual BCR-ABL-positive cells. J Hematol Oncol. 2014;7:37.
Gallipoli P, Cook A, Rhodes S, Hopcroft L, Wheadon H, Whetton AD, et al. JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo. Blood. 2014;124(9):1492-501.
Zacharaki D, Ghazanfari R, Li H, Lim HC, Scheding S. Effects of JAK1/2 inhibition on bone marrow stromal cells of myeloproliferative neoplasm (MPN) patients and healthy individuals. Eur J Haematol. 2018;101(1):57-67.
Guo A, Lu P, Coffey G, Conley P, Pandey A, Wang YL. Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment. Oncotarget. 2017;8(8):12953.
Severin F, Frezzato F, Visentin A, Martini V, Trimarco V, Carraro S, et al. In Chronic Lymphocytic Leukemia the JAK2/STAT3 Pathway Is Constitutively Activated and Its Inhibition Leads to CLL Cell Death Unaffected by the Protective Bone Marrow Microenvironment. Cancers (Basel). 2019;11(12).
Xi Y, Jingying D, Chenglong L, Hong Z, Rong Z, Xiaodong W, et al. Epigenetic Therapy Promotes the Ratio of Th1/Th17 Lineage to Reverse Immune Evasion and Treat Leukemia Relapse Post-allogeneic Stem Cell Transplantation in Non-APL AML Patients. Front Mol Biosci. 2020;7:595395.
Liu K, Wu Z, Chu J, Yang L, Wang N. Promoter methylation and expression of SOCS3 affect the clinical outcome of pediatric acute lymphoblastic leukemia by JAK/STAT pathway. Biomed Pharmacother. 2019;115:108913.
Moskowitz AJ, Ghione P, Jacobsen E, Ruan J, Schatz JH, Noor S, et al. A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood. 2021;138(26):2828-37.
Benyoucef A, Haigh K, Cuddihy A, Haigh JJ. JAK/BCL2 inhibition acts synergistically with LSD1 inhibitors to selectively target ETP-ALL. Leukemia. 2022;36(12):2802-16.
Lim FQ, Chan AS, Yokomori R, Huang XZ, Theardy MS, Yeoh AEJ, et al. Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia. Haematologica. 2023;108(2):367-81.
Trojani A, Pungolino E, Dal Molin A, Lodola M, Rossi G, D'Adda M, et al. Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment. PLoS One. 2019;14(7):e0218444.
Zhang PP, Zhang F, Zhu K, Zhu JF, Yuan Y, Yang YL, et al. Matrine exerted an anti-tumor effect on acute myeloid leukemia via the lncRNA LINC01116/miR-592-mediated JAK/STAT pathway inactivation. Neoplasma. 2022;69(1):123-35.
Byrne M, Savani BN, Mohty M, Nagler A. Peripheral blood stem cell versus bone marrow transplantation: A perspective from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Exp Hematol. 2016;44(7):567-73.
Atsuta Y, Kato S, Morishima Y, Ohashi K, Fukuda T, Ozawa Y, et al. Comparison of HLA Allele Mismatch and Antigen Mismatch in Unrelated Bone Marrow Transplantation in Patients with Leukemia. Biol Blood Marrow Transplant. 2019;25(3):436-42.
Zhang C, Zhang X, Chen XH. Cellular mechanism for granulocyte-colony stimulating factor in the prevention of graft-versus-host disease in combined bone marrow and peripheral blood transplantation for hematological malignancies: the composition in collection. Transfus Apher Sci. 2013;48(1):3-9.
Yuan Y, Tan S, Wang H, Zhu J, Li J, Zhang P, et al. Mesenchymal Stem Cell-Derived Exosomal miRNA-222-3p Increases Th1/Th2 Ratio and Promotes Apoptosis of Acute Myeloid Leukemia Cells. Anal Cell Pathol (Amst). 2023;2023:4024887.
Wei X, He L, Wang X, Lin M, Dai J. Effects of dasatinib on CD8(+)T, Th1, and Treg cells in patients with chronic myeloid leukemia. J Int Med Res. 2020;48(2):300060519877321.
Wang SL, Dong QF, Li F, Wang J, Sang YQ, Zhang L. [Treg Cells, FoxP3 and TGF-β Expression and Significance in Chronic Myeloid Leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2023;31(3):666-70.
El-Maadawy EA, Elshal MF, Bakry RM, Moussa MM, El-Naby S, Talaat RM. Regulation of CD4(+)CD25(+)FOXP3(+) cells in Pediatric Acute Lymphoblastic Leukemia (ALL): Implication of cytokines and miRNAs. Mol Immunol. 2020;124:1-8.
Kelley TW, Parker CJ. CD4 (+)CD25 (+)Foxp3 (+) regulatory T cells and hematologic malignancies. Front Biosci (Schol Ed). 2010;2(3):980-92.

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JAK/STAT signaling pathway inhibitors for leukemia therapeutic potential : a systematic review on in vitro literatures

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Abstract

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Introduction

Method

o Protocol and registration

o Eligibility criteria and search strategy

o Data extraction, Study selection and methodological quality assessment

Results

• Study process

Discussion

Conclusion

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References

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Supplementary Files

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Version 1