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image of Recurrent Missense Driver STAT5B N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia and its In silico Inhibition

Abstract

Background

The occurrence of gain of function mutations in has been associated to survival, and drug resistance in Leukemia. screening of compounds having inhibitory potential towards mutated proteins, can be helpful in the development of specific inhibitors.

Objective

This study was designed to screen selected mutations in leukemia patients and virtual exploration of molecular interaction of potential inhibitors with their mutated products.

Methods

In total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1V623A, JAK2 S473 and STAT5BN642H were screened through allele specific PCR. analysis was performed on wild type and mutant protein sequences retrieved from Protein databank. The ligands and protein were prepared through standard protocols, and docking was performed through Auto Dock Vina 1.2.0.

Results

Acute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1V623A, JAK2 S473 major allele. However, 6 patients (5 male, 1 female) with ALL were STAT5BN642H+. The molecular docking of the ligands to wild type and STAT5BN642H+revealed that AC-4-130, Pimozide, Indirubin and Stafib-2 have higher but differential docking affinities for SH2-domain of both normal and mutated . However, AC-4-130 has a higher affinity for wild type and Stafib-2 has stable molecular interaction with STAT5BN642H+.

Conclusion

The aggressive form of pediatric leukemia, carrying STAT5BN642H mutation is identified in the studied population. It is predicted that AC-14-30 and stafib-2 have potential for inhibition of constitutively active STAT5B if optimized for use in combination therapy.

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2025-03-26

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References

  1. Maurer B. Kollmann S. Pickem J. Hoelbl-Kovacic A. Sexl V. STAT5A and STAT5B—Twins with Different Personalities in Hematopoiesis and Leukemia. Cancers (Basel) 2019 11 11 1726 10.3390/cancers11111726 31690038
    [Google Scholar]
  2. Hammarén H.M. Virtanen A.T. Raivola J. Silvennoinen O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine 2019 118 48 63 10.1016/j.cyto.2018.03.041 29685781
    [Google Scholar]
  3. Villarino A.V. Kanno Y. O’Shea J.J. Mechanisms and consequences of Jak–STAT signaling in the immune system. Nat. Immunol. 2017 18 4 374 384 10.1038/ni.3691 28323260
    [Google Scholar]
  4. Waldmann T.A. Chen J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis: Implications for immunotherapy. Annu. Rev. Immunol. 2017 35 1 533 550 10.1146/annurev‑immunol‑110416‑120628 28182501
    [Google Scholar]
  5. Murray P.J. The JAK-STAT signaling pathway: input and output integration. J. Immunol. 2007 178 5 2623 2629 10.4049/jimmunol.178.5.2623 17312100
    [Google Scholar]
  6. Owen K.L. Brockwell N.K. Parker B.S. JAK-STAT signaling: A double-edged sword of immune regulation and cancer progression. Cancers (Basel) 2019 11 12 2002 10.3390/cancers11122002 31842362
    [Google Scholar]
  7. Matutes E. The 2017 WHO update on mature T‐ and natural killer (NK) cell neoplasms. Int. J. Lab. Hematol. 2018 40 S1 Suppl. 1 97 103 10.1111/ijlh.12817 29741263
    [Google Scholar]
  8. Shahmarvand N. Nagy A. Shahryari J. Ohgami R.S. Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci. 2018 109 4 926 933 10.1111/cas.13525 29417693
    [Google Scholar]
  9. de Araujo E.D. Orlova A. Neubauer H.A. Bajusz D. Seo H.S. Dhe-Paganon S. Keserű G.M. Moriggl R. Gunning P.T. Structural implications of STAT3 and STAT5 SH2 domain mutations. Cancers (Basel) 2019 11 11 1757 10.3390/cancers11111757 31717342
    [Google Scholar]
  10. de Araujo E.D. Erdogan F. Neubauer H.A. Meneksedag-Erol D. Manaswiyoungkul P. Eram M.S. Seo H.S. Qadree A.K. Israelian J. Orlova A. Suske T. Pham H.T.T. Boersma A. Tangermann S. Kenner L. Rülicke T. Dong A. Ravichandran M. Brown P.J. Audette G.F. Rauscher S. Dhe-Paganon S. Moriggl R. Gunning P.T. Structural and functional consequences of the STAT5BN642H driver mutation. Nat. Commun. 2019 10 1 2517 10.1038/s41467‑019‑10422‑7 31175292
    [Google Scholar]
  11. Halim C.E. Deng S. Ong M.S. Yap C.T. Involvement of STAT5 in oncogenesis. Biomedicines 2020 8 9 316 10.3390/biomedicines8090316 32872372
    [Google Scholar]
  12. Wan P. He X. Han Y. Wang L. Yuan Z. Stat5 inhibits NLRP3 ‐mediated pyroptosis to enhance chemoresistance of breast cancer cells via promoting miR ‐182 transcription. Chem. Biol. Drug Des. 2023 102 1 14 25 10.1111/cbdd.14229 36905318
    [Google Scholar]
  13. Bhattacharya D. Teramo A. Gasparini V.R. Huuhtanen J. Kim D. Theodoropoulos J. Schiavoni G. Barilà G. Vicenzetto C. Calabretto G. Facco M. Kawakami T. Nakazawa H. Falini B. Tiacci E. Ishida F. Semenzato G. Kelkka T. Zambello R. Mustjoki S. Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia. Blood Cancer J. 2022 12 2 31 10.1038/s41408‑022‑00630‑8 35210405
    [Google Scholar]
  14. Raj S. Sasidharan S. Dubey V.K. Saudagar P. Identification of lead molecules against potential drug target protein MAPK4 from L. donovani: An in-silico approach using docking, molecular dynamics and binding free energy calculation. PLoS One 2019 14 8 e0221331 10.1371/journal.pone.0221331 31425543
    [Google Scholar]
  15. Hughes J.P. Rees S. Kalindjian S.B. Philpott K.L. Principles of early drug discovery. Br. J. Pharmacol. 2011 162 6 1239 1249 10.1111/j.1476‑5381.2010.01127.x 21091654
    [Google Scholar]
  16. Chen D. Oezguen N. Urvil P. Ferguson C. Dann S.M. Savidge T.C. Regulation of protein-ligand binding affinity by hydrogen bond pairing. Sci. Adv. 2016 2 3 e1501240 10.1126/sciadv.1501240 27051863
    [Google Scholar]
  17. Kumar Y. Singh H. Patel C.N. In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing. J. Infect. Public Health 2020 13 9 1210 1223 10.1016/j.jiph.2020.06.016 32561274
    [Google Scholar]
  18. Hall D.C. Jr Ji H.F. A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Med. Infect. Dis. 2020 35 101646 10.1016/j.tmaid.2020.101646 32294562
    [Google Scholar]
  19. Rahman F. Tabrez S. Ali R. Alqahtani A.S. Ahmed M.Z. Rub A. Molecular docking analysis of rutin reveals possible inhibition of SARS-CoV-2 vital proteins. J. Tradit. Complement. Med. 2021 11 2 173 179 10.1016/j.jtcme.2021.01.006 33520682
    [Google Scholar]
  20. Alnajjar R. Mostafa A. Kandeil A. Al-Karmalawy A.A. Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease. Heliyon 2020 6 12 e05641 10.1016/j.heliyon.2020.e05641 33294721
    [Google Scholar]
  21. Bhattacharya K. Bordoloi R. Chanu N.R. Kalita R. Sahariah B.J. Bhattacharjee A. In silico discovery of 3 novel quercetin derivatives against papain-like protease, spike protein, and 3C-like protease of SARS-CoV-2. J. Genet. Eng. Biotechnol. 2022 20 1 43 10.1186/s43141‑022‑00314‑7 35262828
    [Google Scholar]
  22. Parks J. Smith J. Clinical implications of basic research how to discover. Antivir. Drugs Quickl. 2020 2020 1 4
    [Google Scholar]
  23. Pham H.T.T. Maurer B. Prchal-Murphy M. Grausenburger R. Grundschober E. Javaheri T. Nivarthi H. Boersma A. Kolbe T. Elabd M. Halbritter F. Pencik J. Kazemi Z. Grebien F. Hengstschläger M. Kenner L. Kubicek S. Farlik M. Bock C. Valent P. Müller M. Rülicke T. Sexl V. Moriggl R. STAT5BN642H is a driver mutation for T cell neoplasia. J. Clin. Invest. 2017 128 1 387 401 10.1172/JCI94509 29200404
    [Google Scholar]
  24. Diop A. Santorelli D. Malagrinò F. Nardella C. Pennacchietti V. Pagano L. Marcocci L. Pietrangeli P. Gianni S. Toto A. SH2 domains: folding, binding and therapeutical approaches. Int. J. Mol. Sci. 2022 23 24 15944 10.3390/ijms232415944 36555586
    [Google Scholar]
  25. Keilhack H. David F.S. McGregor M. Cantley L.C. Neel B.G. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J. Biol. Chem. 2005 280 35 30984 30993 10.1074/jbc.M504699200 15987685
    [Google Scholar]
  26. Niihori T. Aoki Y. Ohashi H. Kurosawa K. Kondoh T. Ishikiriyama S. Kawame H. Kamasaki H. Yamanaka T. Takada F. Nishio K. Sakurai M. Tamai H. Nagashima T. Suzuki Y. Kure S. Fujii K. Imaizumi M. Matsubara Y. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J. Hum. Genet. 2005 50 4 192 202 10.1007/s10038‑005‑0239‑7 15834506
    [Google Scholar]
  27. Bandapalli O.R. Schuessele S. Kunz J.B. Rausch T. Stütz A.M. Tal N. Geron I. Gershman N. Izraeli S. Eilers J. The activating STAT5B N642H mutation is a common abnormality in pediatric T-cell acute lymphoblastic leukemia and confers a higher risk of relapse. Haematologica 2014 99 10 e188
    [Google Scholar]
  28. Kiel M.J. Velusamy T. Rolland D. Sahasrabuddhe A.A. Chung F. Bailey N.G. Schrader A. Li B. Li J.Z. Ozel A.B. Betz B.L. Miranda R.N. Medeiros L.J. Zhao L. Herling M. Lim M.S. Elenitoba-Johnson K.S.J. Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 2014 124 9 1460 1472 10.1182/blood‑2014‑03‑559542 24825865
    [Google Scholar]
  29. Ma X. Wen L. Wu L. Wang Q. Yao H. Wang Q. Ma L. Chen S. Rare occurrence of a STAT5B N642H mutation in adult T-cell acute lymphoblastic leukemia. Cancer Genet. 2015 208 1-2 52 53 10.1016/j.cancergen.2014.12.001 25749351
    [Google Scholar]
  30. Rajala H.L.M. Eldfors S. Kuusanmäki H. van Adrichem A.J. Olson T. Lagström S. Andersson E.I. Jerez A. Clemente M.J. Yan Y. Zhang D. Awwad A. Ellonen P. Kallioniemi O. Wennerberg K. Porkka K. Maciejewski J.P. Loughran T.P. Jr Heckman C. Mustjoki S. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 2013 121 22 4541 4550 10.1182/blood‑2012‑12‑474577 23596048
    [Google Scholar]
  31. Rajala H.L.M. Porkka K. Maciejewski J.P. Loughran T.P. Jr Mustjoki S. Uncovering the pathogenesis of large granular lymphocytic leukemia—novel STAT3 and STAT5b mutations. Ann. Med. 2014 46 3 114 122 10.3109/07853890.2014.882105 24512550
    [Google Scholar]
  32. Luo Q. Shen J. Yang Y. Tang H. Shi M. Liu J. Liu Z. Shi X. Yi Y. CSF3R T618I, ASXL1 G942 fs and STAT5B N642H trimutation co‐contribute to a rare chronic neutrophilic leukaemia manifested by rapidly progressive leucocytosis, severe infections, persistent fever and deep venous thrombosis. Br. J. Haematol. 2018 180 6 892 894 10.1111/bjh.14456 27984641
    [Google Scholar]
  33. Cross N.C.P. Hoade Y. Tapper W.J. Carreno-Tarragona G. Fanelli T. Jawhar M. Naumann N. Pieniak I. Lübke J. Ali S. Bhuller K. Burgstaller S. Cargo C. Cavenagh J. Duncombe A.S. Das-Gupta E. Evans P. Forsyth P. George P. Grimley C. Jack F. Munro L. Mehra V. Patel K. Rismani A. Sciuccati G. Thomas-Dewing R. Thornton P. Virchis A. Watt S. Wallis L. Whiteway A. Zegocki K. Bain B.J. Reiter A. Chase A. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia 2019 33 2 415 425 10.1038/s41375‑018‑0342‑3 30573779
    [Google Scholar]
  34. Babushok D.V. Perdigones N. Perin J.C. Olson T.S. Ye W. Roth J.J. Lind C. Cattier C. Li Y. Hartung H. Paessler M.E. Frank D.M. Xie H.M. Cross S. Cockroft J.D. Podsakoff G.M. Monos D. Biegel J.A. Mason P.J. Bessler M. Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia. Cancer Genet. 2015 208 4 115 128 10.1016/j.cancergen.2015.01.007 25800665
    [Google Scholar]
  35. Hennighausen L. Robinson G.W. Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes Dev. 2008 22 6 711 721 10.1101/gad.1643908 18347089
    [Google Scholar]
  36. Nelson E.A. Walker S.R. Xiang M. Weisberg E. Bar-Natan M. Barrett R. Liu S. Kharbanda S. Christie A.L. Nicolais M. Griffin J.D. Stone R.M. Kung A.L. Frank D.A. The STAT5 inhibitor pimozide displays efficacy in models of acute myelogenous leukemia driven by FLT3 mutations. Genes Cancer 2012 3 7-8 503 511 10.1177/1947601912466555 23264850
    [Google Scholar]
  37. Nam S. Scuto A. Yang F. Chen W. Park S. Yoo H.S. Konig H. Bhatia R. Cheng X. Merz K.H. Eisenbrand G. Jove R. Indirubin derivatives induce apoptosis of chronic myelogenous leukemia cells involving inhibition of Stat5 signaling. Mol. Oncol. 2012 6 3 276 283 10.1016/j.molonc.2012.02.002 22387217
    [Google Scholar]
  38. World Health Organization. Regional Office for the Eastern Mediterranean. (‎2019)‎. Healthy diet. World Health Organization. Regional Office for the Eastern Mediterranean. 2019 Available from:https://iris.who.int/handle/10665/325828 (accessed on 12-11-2024).
  39. Miller S.A. Dykes D.D. Polesky H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988 16 3 1215 10.1093/nar/16.3.1215 3344216
    [Google Scholar]
  40. Brachet-Botineau M. Deynoux M. Vallet N. Polomski M. Juen L. Hérault O. Mazurier F. Viaud-Massuard M.C. Prié G. Gouilleux F. A novel inhibitor of STAT5 signaling overcomes chemotherapy resistance in myeloid leukemia cells. Cancers (Basel) 2019 11 12 2043 10.3390/cancers11122043 31861239
    [Google Scholar]
  41. Cumaraswamy A.A. Lewis A.M. Geletu M. Todic A. Diaz D.B. Cheng X.R. Brown C.E. Laister R.C. Muench D. Kerman K. Grimes H.L. Minden M.D. Gunning P.T. Nanomolar-potency small molecule inhibitor of STAT5 Protein. ACS Med. Chem. Lett. 2014 5 11 1202 1206 10.1021/ml500165r 25419444
    [Google Scholar]
  42. Wingelhofer B. Maurer B. Heyes E.C. Cumaraswamy A.A. Berger-Becvar A. de Araujo E.D. Orlova A. Freund P. Ruge F. Park J. Tin G. Ahmar S. Lardeau C.H. Sadovnik I. Bajusz D. Keserű G.M. Grebien F. Kubicek S. Valent P. Gunning P.T. Moriggl R. Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia 2018 32 5 1135 1146 10.1038/s41375‑017‑0005‑9 29472718
    [Google Scholar]
  43. Su L. David M. Distinct mechanisms of STAT phosphorylation via the interferon-alpha/beta receptor. Selective inhibition of STAT3 and STAT5 by piceatannol. J. Biol. Chem. 2000 275 17 12661 12666 10.1074/jbc.275.17.12661 10777558
    [Google Scholar]
  44. Mistry H. Hsieh G. Buhrlage S.J. Huang M. Park E. Cuny G.D. Galinsky I. Stone R.M. Gray N.S. D’Andrea A.D. Parmar K. Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol. Cancer Ther. 2013 12 12 2651 2662 10.1158/1535‑7163.MCT‑13‑0103‑T 24130053
    [Google Scholar]
  45. Elumalai N. Berg A. Rubner S. Blechschmidt L. Song C. Natarajan K. Matysik J. Berg T. Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b. Sci. Rep. 2017 7 1 819 10.1038/s41598‑017‑00920‑3 28400581
    [Google Scholar]
  46. Pinz S. Unser S. Rascle A. The natural chemopreventive agent sulforaphane inhibits STAT5 activity. PLoS One 2014 9 6 e99391 10.1371/journal.pone.0099391 24910998
    [Google Scholar]
  47. BIOVIA Discovery Studio. 2021 Available from:https://www.3ds.com/products/biovia/discovery-studio (accessed on 12-11-2024).
  48. Eberhardt J. Santos-Martins D. Tillack A.F. Forli S. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings. J. Chem. Inf. Model. 2021 61 8 3891 3898 10.1021/acs.jcim.1c00203 34278794
    [Google Scholar]
  49. Szklarczyk D. Gable A.L. Nastou K.C. Lyon D. Kirsch R. Pyysalo S. Doncheva N.T. Legeay M. Fang T. Bork P. Jensen L.J. von Mering C. The STRING database in 2021: Customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021 49 D1 D605 D612 10.1093/nar/gkaa1074 33237311
    [Google Scholar]
  50. Kavesh M. Mohebnasab M. Angel M.R. Xie W. Raess P.W. Cui W. Press R.D. Yang G. Li P. Distinguishing STAT3/STAT5B -mutated large granular lymphocyte leukemia from myeloid neoplasms by genetic profiling. Blood Adv. 2023 7 1 40 45 10.1182/bloodadvances.2022008192 35939786
    [Google Scholar]
  51. Qu S. Jia Y. Wang H. Ai X. Xu Z. Qin T. Pan L. Li B. Huang G. Gale R.P. Xiao Z. STAT3 and STAT5B mutations have unique distribution in T-cell large granular lymphocyte proliferations and advanced myeloid neoplasms. Leuk. Lymphoma 2021 62 6 1506 1509 10.1080/10428194.2020.1869964 33410350
    [Google Scholar]
  52. Andersson E.I. Tanahashi T. Sekiguchi N. Gasparini V.R. Bortoluzzi S. Kawakami T. Matsuda K. Mitsui T. Eldfors S. Bortoluzzi S. Coppe A. Binatti A. Lagström S. Ellonen P. Fukushima N. Nishina S. Senoo N. Sakai H. Nakazawa H. Kwong Y.L. Loughran T.P. Maciejewski J.P. Mustjoki S. Ishida F. High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. Blood 2016 128 20 2465 2468 10.1182/blood‑2016‑06‑724856 27697773
    [Google Scholar]
  53. Umrau K. Naganuma K. Gao Q. Dogan A. Kizaki M. Roshal M. Liu Y. Yabe M. Activating STAT5B mutations can cause both primary hypereosinophilia and lymphocyte-variant hypereosinophilia. Leuk. Lymphoma 2023 64 1 238 241 10.1080/10428194.2022.2131413 36308018
    [Google Scholar]
  54. Bourgeais J. Ishac N. Medrzycki M. Brachet-Botineau M. Desbourdes L. Gouilleux-Gruart V. Pecnard E. Rouleux-Bonnin F. Gyan E. Domenech J. Mazurier F. Moriggl R. Bunting K.D. Herault O. Gouilleux F. Oncogenic STAT5 signaling promotes oxidative stress in chronic myeloid leukemia cells by repressing antioxidant defenses. Oncotarget 2017 8 26 41876 41889 10.18632/oncotarget.11480 27566554
    [Google Scholar]
  55. Hu Z. Medeiros L.J. Xu M. Yuan J. Peker D. Shao L. Tang Z. Mai B. Thakral B. Rios A. Hu S. Wang W. T-cell prolymphocytic leukemia with t(X;14)(q28;q11.2): A clinicopathologic study of 15 cases. Am. J. Clin. Pathol. 2023 159 4 325 336 10.1093/ajcp/aqac166 36883805
    [Google Scholar]
  56. Suske T. Sorger H. Manhart G. Ruge F. Prutsch N. Zimmerman M.W. Eder T. Abdallah D.I. Maurer B. Wagner C. Schönefeldt S. Spirk K. Pichler A. Pemovska T. Schweicker C. Pölöske D. Hubanic E. Jungherz D. Müller T.A. Aung M.M.K. Orlova A. Pham H.T.T. Zimmel K. Krausgruber T. Bock C. Müller M. Dahlhoff M. Boersma A. Rülicke T. Fleck R. de Araujo E.D. Gunning P.T. Aittokallio T. Mustjoki S. Sanda T. Hartmann S. Grebien F. Hoermann G. Haferlach T. Staber P.B. Neubauer H.A. Look A.T. Herling M. Moriggl R. Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia. J. Clin. Invest. 2024 134 8 e168536 10.1172/JCI168536 38618957
    [Google Scholar]
  57. Neubauer H.A. Suske T. Schönefeldt S. Tangermann S. Boersma A. Rülicke T. Bekiaris V. Kenner L. Moriggl R. Abstract 2752: The gain-of-function STAT5BN642H mutation as a driver of mature T cell leukemia/lymphoma. Cancer Res. 2020 80 16 Supl 2752 2752 10.1158/1538‑7445.AM2020‑2752
    [Google Scholar]
  58. Ullah F. Markouli M. Orland M. Ogbue O. Dima D. Omar N. Mustafa Ali M.K. Large granular lymphocytic leukemia: Clinical features, molecular pathogenesis, diagnosis and treatment. Cancers (Basel) 2024 16 7 1307 10.3390/cancers16071307 38610985
    [Google Scholar]
  59. Klein K. Kollmann S. Hiesinger A. List J. Kendler J. Klampfl T. Rhandawa M. Trifinopoulos J. Maurer B. Grausenburger R. Betram C.A. Moriggl R. Rülicke T. Mullighan C.G. Witalisz-Siepracka A. Walter W. Hoermann G. Sexl V. Gotthardt D. A lineage-specific STAT5B N642H mouse model to study NK-cell leukemia. Blood 2024 143 24 2474 2489 10.1182/blood.2023022655 38498036
    [Google Scholar]
  60. Yin C.C. Tam W. Walker S.M. Kaur A. Ouseph M.M. Xie W. K Weinberg O. Li P. Zuo Z. Routbort M.J. Chen S. Medeiros L.J. George T.I. Orazi A. Arber D.A. Bagg A. Hasserjian R.P. Wang S.A. STAT5B mutations in myeloid neoplasms differ by disease subtypes but characterize a subset of chronic myeloid neoplasms with eosinophilia and/or basophilia. Haematologica 2024 109 6 1825 1835 37981812
    [Google Scholar]
  61. Ullah S. Tonks A. A Halawi M. A M A. Alkuwaykibi M. Halawi A. Hayat A. Alkoumi H.A.H. Alanzi M. Wadood A. Whole exome sequence of Pakistani acute lymphocytic leukemia patient from Pakhtuns ancestry reveal the novel genetic variant characterization in the GLDC gene. J. Biotechnol. Biomed. 2023 6 3 409 420 10.26502/jbb.2642‑91280103
    [Google Scholar]
  62. Ahmed Z.A. Nasir A. Sheikh M.S. Rizvi A.Q. Moatter T. Characteristics of BCR-ABL rearrangement variants in Pakistani patients with chronic myeloid leukemia and acute lymphocytic leukemia. Ann. Oncol. 2019 30 ix94 10.1093/annonc/mdz427.011
    [Google Scholar]
  63. Shahid S. Shakeel M. Siddiqui S. Ahmed S. Sohail M. Khan I.A. Abid A. Shamsi T. Novel genetic variations in acute myeloid leukemia in Pakistani population. Front. Genet. 2020 11 560 10.3389/fgene.2020.00560 32655615
    [Google Scholar]
  64. Shabih Haider Mahmood A. AKhtar F. Mahmood R. Muzafar S. Batool M. BCR-ABL1 Gene mutation in acute lymphoblastic leukemia. Annal. PIMS-Shaheed Zulfiqar Ali Bhutto Med. Uni. 2022 18 3 181 185 10.48036/apims.v18i3.629
    [Google Scholar]
  65. Azad A.K. Khan M.R. Habib A.B.M.H. Miah M.A.W. Begum M. Aberrant expression of CD markers in acute myeloid leukaemia. Haematol. J. Bangladesh 2020 2 1 14 16 10.37545/haematoljbd201812
    [Google Scholar]
  66. Faiz M. Azeem M. Qureshi A. Incidence of flt3-itd gene mutations among pakistani patients with acute lymphoblastic leukemia patients: A preliminary study. Int. J. Med. Lab Res. 2018 3 2 1 6
    [Google Scholar]
  67. Corsello S.M. Bittker J.A. Liu Z. Gould J. McCarren P. Hirschman J.E. Johnston S.E. Vrcic A. Wong B. Khan M. Asiedu J. Narayan R. Mader C.C. Subramanian A. Golub T.R. The Drug Repurposing Hub: A next-generation drug library and information resource. Nat. Med. 2017 23 4 405 408 10.1038/nm.4306 28388612
    [Google Scholar]
  68. Ghanem A. Emara H.A. Muawia S. Abd El Maksoud A.I. Al-Karmalawy A.A. Elshal M.F. Tanshinone IIA synergistically enhances the antitumor activity of doxorubicin by interfering with the PI3K/AKT/mTOR pathway and inhibition of topoisomerase II: in vitro and molecular docking studies. New J. Chem. 2020 44 40 17374 17381 10.1039/D0NJ04088F
    [Google Scholar]
  69. Eliaa S.G. Al-Karmalawy A.A. Saleh R.M. Elshal M.F. Empagliflozin and doxorubicin synergistically inhibit the survival of triple-negative breast cancer cells via interfering with the mtor pathway and inhibition of calmodulin: In vitro and molecular docking studies. ACS Pharmacol. Transl. Sci. 2020 3 6 1330 1338 10.1021/acsptsci.0c00144 33344906
    [Google Scholar]
  70. Barrows N. Campos R. Powell S. Prasanth K. Schott-Lerner G. Soto-Acosta R. A screen of FDA-approved drugs for inhibitors of zika virus infection. Cell Host Microbe. 2016 20 2 259 270
    [Google Scholar]
  71. Tremblay C.S. Saw J. Boyle J.A. Haigh K. Litalien V. McCalmont H.R. Evans K. Lock R.B. Jane S.M. Haigh J.J. Curtis D.J. STAT5 activation promotes progression and chemotherapy-resistance in early T-cell precursor acute lymphoblastic leukemia. Blood 2023 142 3 blood.2022016322 10.1182/blood.2022016322 36989489
    [Google Scholar]
  72. Nelson E.A. Walker S.R. Weisberg E. Bar-Natan M. Barrett R. Gashin L.B. Terrell S. Klitgaard J.L. Santo L. Addorio M.R. Ebert B.L. Griffin J.D. Frank D.A. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood 2011 117 12 3421 3429 10.1182/blood‑2009‑11‑255232 21233313
    [Google Scholar]
  73. Walker S.R. Xiang M. Frank D.A. Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer. Mol. Cell. Endocrinol. 2014 382 1 616 621 10.1016/j.mce.2013.03.010 23531638
    [Google Scholar]
  74. Simpson H.M. Furusawa A. Sadashivaiah K. Civin C.I. Banerjee A. STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma. Oncotarget 2018 9 24 16792 16806 10.18632/oncotarget.24698 29682185
    [Google Scholar]
/content/journals/acamc/10.2174/0118715206350463241226032324
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Recurrent Missense Driver STAT5B N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia and its In silico Inhibition
Bentham Science Publishers ; https://doi.org/10.2174/0118715206350463241226032324
/content/journals/acamc/10.2174/0118715206350463241226032324
/content/journals/acamc/10.2174/0118715206350463241226032324
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Visual 3D structural overlay of SH2 domains docx The list of IUPAC names and chemical structure and Structure of the selected ligands for STAT5B interaction docx. Mutational status of JAK1V623A, JAK2S473 and STAT5BN642Hin leukemia docx. Supplementary material is available on the publisher's website along with the published article.

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  • Article Type:     Research Article
Keywords: stafib-2 ; targeted inhibition ; AC-4-130 ; aggressive leukemia ; personalized therapy ; STAT5BN642H

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