Research progress of Janus kinase-signal transduction and activator of transcription signaling pathway related gene mutations in acute leukemia_West China Medical Journal

Authors：

HUANG Shijin ¹ ,  YANG Jie ² , XU Xiaoyan ¹ , LIU Jingyue ³

1. Graduate School, Hebei North University, Zhangjiakou, Hebei 075000, P. R. China;
2. Department of Hematology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P. R. China;
3. Department of Hematology, South District of the Fifth Medical Center of PLA General Hospital, Beijing 100071, P. R. China;

Corresponding author：

YANG Jie, Email: yjyyb@163.com

Keywords：

Janus kinase-signal transduction and activator of transcription signaling pathway; acute leukemia; SH2B3

DOI：

10.7507/1002-0179.202404069

Video：

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Continuous activation of Janus kinase (JAK)- signal transduction and activator of transcription (STAT) signaling pathway is prevalent in leukemia cells, and it has been found that this pathway plays an important role in acute leukemia (AL). JAK2/JAK1 gene mutations are found in both acute myelocytic leukemia and acute lymphoblastic leukemia and may have implications for the treatment and overall prognosis of the disease. Among the STAT family members, STAT3 and STAT5 proved to be key factors in AL. These gene mutations may provide new targets and new ideas for the treatment of AL. This article provides a review of the research progress of JAK-STAT signaling pathway, related gene mutations and AL.

Citation： HUANG Shijin, YANG Jie, XU Xiaoyan, LIU Jingyue. Research progress of Janus kinase-signal transduction and activator of transcription signaling pathway related gene mutations in acute leukemia. West China Medical Journal, 2024, 39(8): 1308-1313. doi: 10.7507/1002-0179.202404069 Copy

1.	康亚伟, 钦东煜, 罗广立. 桦木酸通过 JAK2/STAT3 信号通路对白血病细胞增殖和凋亡的影响. 实用癌症杂志, 2023, 38(11): 1750-1753.
2.	Fasouli ES, Katsantoni E. JAK-STAT in early hematopoiesis and leukemia. Front Cell Dev Biol, 2021, 9: 669363.
3.	袁小庚, 万润涛, 赵晓武, 等. 共表达 BCR-ABL1 与 JAK2 V617F 的骨髓增殖性肿瘤患者实验室及临床特征分析. 中国实验血液学杂志, 2021, 29(4): 1236-1241.
4.	Hidalgo-López JE, Kanagal-Shamanna R, Medeiros LJ, et al. Morphologic and molecular characteristics of de novo AML With JAK2 V617F mutation. J Natl Compr Canc Netw, 2017, 15(6): 790-796.
5.	Zhou S, Tremblay D, Hoffman R, et al. Clinical benefit derived from decitabine therapy for advanced phases of myeloproliferative neoplasms. Acta Haematol, 2021, 144(1): 48-57.
6.	Rah B, Rather RA, Bhat GR, et al. JAK/STAT signaling: molecular targets, therapeutic opportunities, and limitations of targeted inhibitions in solid malignancies. Front Pharmacol, 2022, 13: 821344.
7.	Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol, 1998, 16: 293-322.
8.	Lee HJ, Daver N, Kantarjian HM, et al. The role of JAK pathway dysregulation in the pathogenesis and treatment of acute myeloid leukemia. Clin Cancer Res, 2013, 19(2): 327-335.
9.	段一菲, 文飞球. STAT5 与儿童急性淋巴细胞白血病关系的研究进展. 中国当代儿科杂志, 2022, 24(8): 942-947.
10.	Zhou J, Chng WJ. Biological hallmarks and emerging strategies to target STAT3 signaling in multiple myeloma. Cells, 2022, 11(6): 941.
11.	Namanja AT, Wang J, Buettner R, et al. Allosteric communication across STAT3 domains associated with STAT3 function and disease-causing mutation. J Mol Biol, 2016, 428(3): 579-589.
12.	徐娜娜, 吴涛, 寇明坤, 等. JAK2 基因突变在急性髓细胞白血病中的研究进展. 诊断学理论与实践, 2020, 19(2): 195-198.
13.	Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol, 2012, 83(9): 1136-1145.
14.	Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders. Pharmacol Res, 2022, 183: 106362.
15.	Xue C, Yao Q, Gu X, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther, 2023, 8(1): 204.
16.	Venugopal S, Bar-Natan M, Mascarenhas JO. JAKs to STATs: a tantalizing therapeutic target in acute myeloid leukemia. Blood Rev, 2020, 40: 100634.
17.	Seif F, Khoshmirsafa M, Aazami H, et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal, 2017, 15(1): 23.
18.	Moser B, Edtmayer S, Witalisz-Siepracka A, et al. The ups and downs of STAT inhibition in acute myeloid leukemia. Biomedicines, 2021, 9(8): 1051.
19.	Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med, 2005, 352(17): 1779-1790.
20.	Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene, 2006, 25(9): 1434-1436.
21.	Illmer T, Schaich M, Ehninger G, et al. Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. Haematologica, 2007, 92(1): 137-138.
22.	Aynardi J, Manur R, Hess PR, et al. JAK2 V617F-positive acute myeloid leukaemia (AML): a comparison between de novo AML and secondary AML transformed from an underlying myeloproliferative neoplasm. A study from the bone marrow pathology group. Br J Haematol, 2018, 182(1): 78-85.
23.	Fröhling S, Lipka DB, Kayser S, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood, 2006, 107(3): 1242-1243.
24.	沈益民, 晁红颖, 张日, 等. 80 例急性髓性白血病 M2 型患者 JAK2V617F 基因突变的检测及临床意义. 中华肿瘤杂志, 2009, 31(5): 366-370.
25.	Haan C, Rolvering C, Raulf F, et al. Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem Biol, 2011, 18(3): 314-323.
26.	Mullighan C, Zhang J, Harvey R. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA, 2009, 106(23): 9414-9418.
27.	Sun X, Liu X, Li Y, et al. Characteristics of molecular genetic mutations and their correlation with prognosis in adolescent and adult patients with acute lymphoblastic leukemia. Oncology, 2024, 102(1): 85-98.
28.	Kołodrubiec J, Kozłowska M, Irga-Jaworska N, et al. Efficacy of ruxolitinib in acute lymphoblastic leukemia: a systematic review. Leuk Res, 2022, 121: 106925.
29.	Loh CY, Arya A, Naema AF, et al. Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol, 2019, 9: 48.
30.	Amaya ML, Inguva A, Pei S, et al. The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation. Blood, 2022, 139(4): 584-596.
31.	Tan M, Rong Y, Su Q, et al. Artesunate induces apoptosis via inhibition of STAT3 in THP-1 cells. Leuk Res, 2017, 62: 98-103.
32.	Shi Y, Zhang Z, Qu X, et al. Roles of STAT3 in leukemia (Review). Int J Oncol, 2018, 53(1): 7-20.
33.	Stevens AM, Ruiz MJ, Gerbing RB, et al. Ligand-induced STAT3 signaling increases at relapse and is associated with outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Haematologica, 2015, 100(12): e496-e500.
34.	赵培伟, 乐鑫, 熊昊, 等. STAT3 基因与儿童急性淋巴细胞白血病的相关性. 中华实用儿科临床杂志, 2016, 31(15): 1152-1155.
35.	贾祝霞, 卢绪章, 蔡晓辉, 等. STAT3 磷酸化介导白血病细胞对多柔比星耐药的机制研究. 中华血液学杂志, 2020, 41(1): 69-71.
36.	Smith MR, Satter LRF, Vargas-Hernández A. STAT5b: a master regulator of key biological pathways. Front Immunol, 2022, 13: 1025373.
37.	Arfeuille C, Vial Y, Cadenet M, et al. Germline bi-allelic SH2B3/LNK alteration predisposes to a neonatal juvenile myelomonocytic leukemia-like disorder. Haematologica, 2024, 109(8): 2542-2554.
38.	Morris R, Butler L, Perkins A, et al. The role of LNK (SH2B3) in the regulation of JAK-STAT signalling in haematopoiesis. Pharmaceuticals (Basel), 2021, 15(1): 24.
39.	Lundin Ström KB, Biloglav A, Castor A, et al. Acquired uniparental isodisomies involving chromosome 12 in paediatric B‐cell precursor acute lymphoblastic leukaemia: associations with chromosome 21 gains and SH2B3 mutations. Br J Haematol, 2023, 201(3): 585-588.
40.	陈烈欢, 程龙庆, 彭翔, 等. SH2B1 沉默对胃癌 SGC-7901 细胞增殖、凋亡及 PI3K/AKT 通路的影响. 检验医学与临床, 2020, 17(3): 354-357, 362.
41.	Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood, 2013, 122(14): 2425-2432.
42.	吴柳松, 韩春生, 谭梅, 等. LNK 基因单核苷酸多态性与急性白血病易感性研究. 中国实验血液学杂志, 2016, 24(5): 1305-1311.
43.	罗茜, 谭梅, 吴柳松, 等. LNK 基因在急性白血病患者中的表达及临床意义. 中国实验血液学杂志, 2018, 26(2): 317-323.

1. 康亚伟, 钦东煜, 罗广立. 桦木酸通过 JAK2/STAT3 信号通路对白血病细胞增殖和凋亡的影响. 实用癌症杂志, 2023, 38(11): 1750-1753.
2. Fasouli ES, Katsantoni E. JAK-STAT in early hematopoiesis and leukemia. Front Cell Dev Biol, 2021, 9: 669363.
3. 袁小庚, 万润涛, 赵晓武, 等. 共表达 BCR-ABL1 与 JAK2 V617F 的骨髓增殖性肿瘤患者实验室及临床特征分析. 中国实验血液学杂志, 2021, 29(4): 1236-1241.
4. Hidalgo-López JE, Kanagal-Shamanna R, Medeiros LJ, et al. Morphologic and molecular characteristics of de novo AML With JAK2 V617F mutation. J Natl Compr Canc Netw, 2017, 15(6): 790-796.
5. Zhou S, Tremblay D, Hoffman R, et al. Clinical benefit derived from decitabine therapy for advanced phases of myeloproliferative neoplasms. Acta Haematol, 2021, 144(1): 48-57.
6. Rah B, Rather RA, Bhat GR, et al. JAK/STAT signaling: molecular targets, therapeutic opportunities, and limitations of targeted inhibitions in solid malignancies. Front Pharmacol, 2022, 13: 821344.
7. Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol, 1998, 16: 293-322.
8. Lee HJ, Daver N, Kantarjian HM, et al. The role of JAK pathway dysregulation in the pathogenesis and treatment of acute myeloid leukemia. Clin Cancer Res, 2013, 19(2): 327-335.
9. 段一菲, 文飞球. STAT5 与儿童急性淋巴细胞白血病关系的研究进展. 中国当代儿科杂志, 2022, 24(8): 942-947.
10. Zhou J, Chng WJ. Biological hallmarks and emerging strategies to target STAT3 signaling in multiple myeloma. Cells, 2022, 11(6): 941.
11. Namanja AT, Wang J, Buettner R, et al. Allosteric communication across STAT3 domains associated with STAT3 function and disease-causing mutation. J Mol Biol, 2016, 428(3): 579-589.
12. 徐娜娜, 吴涛, 寇明坤, 等. JAK2 基因突变在急性髓细胞白血病中的研究进展. 诊断学理论与实践, 2020, 19(2): 195-198.
13. Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol, 2012, 83(9): 1136-1145.
14. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders. Pharmacol Res, 2022, 183: 106362.
15. Xue C, Yao Q, Gu X, et al. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther, 2023, 8(1): 204.
16. Venugopal S, Bar-Natan M, Mascarenhas JO. JAKs to STATs: a tantalizing therapeutic target in acute myeloid leukemia. Blood Rev, 2020, 40: 100634.
17. Seif F, Khoshmirsafa M, Aazami H, et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal, 2017, 15(1): 23.
18. Moser B, Edtmayer S, Witalisz-Siepracka A, et al. The ups and downs of STAT inhibition in acute myeloid leukemia. Biomedicines, 2021, 9(8): 1051.
19. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med, 2005, 352(17): 1779-1790.
20. Lee JW, Kim YG, Soung YH, et al. The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene, 2006, 25(9): 1434-1436.
21. Illmer T, Schaich M, Ehninger G, et al. Tyrosine kinase mutations of JAK2 are rare events in AML but influence prognosis of patients with CBF-leukemias. Haematologica, 2007, 92(1): 137-138.
22. Aynardi J, Manur R, Hess PR, et al. JAK2 V617F-positive acute myeloid leukaemia (AML): a comparison between de novo AML and secondary AML transformed from an underlying myeloproliferative neoplasm. A study from the bone marrow pathology group. Br J Haematol, 2018, 182(1): 78-85.
23. Fröhling S, Lipka DB, Kayser S, et al. Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7. Blood, 2006, 107(3): 1242-1243.
24. 沈益民, 晁红颖, 张日, 等. 80 例急性髓性白血病 M2 型患者 JAK2V617F 基因突变的检测及临床意义. 中华肿瘤杂志, 2009, 31(5): 366-370.
25. Haan C, Rolvering C, Raulf F, et al. Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem Biol, 2011, 18(3): 314-323.
26. Mullighan C, Zhang J, Harvey R. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA, 2009, 106(23): 9414-9418.
27. Sun X, Liu X, Li Y, et al. Characteristics of molecular genetic mutations and their correlation with prognosis in adolescent and adult patients with acute lymphoblastic leukemia. Oncology, 2024, 102(1): 85-98.
28. Kołodrubiec J, Kozłowska M, Irga-Jaworska N, et al. Efficacy of ruxolitinib in acute lymphoblastic leukemia: a systematic review. Leuk Res, 2022, 121: 106925.
29. Loh CY, Arya A, Naema AF, et al. Signal transducer and activator of transcription (STATs) proteins in cancer and inflammation: functions and therapeutic implication. Front Oncol, 2019, 9: 48.
30. Amaya ML, Inguva A, Pei S, et al. The STAT3-MYC axis promotes survival of leukemia stem cells by regulating SLC1A5 and oxidative phosphorylation. Blood, 2022, 139(4): 584-596.
31. Tan M, Rong Y, Su Q, et al. Artesunate induces apoptosis via inhibition of STAT3 in THP-1 cells. Leuk Res, 2017, 62: 98-103.
32. Shi Y, Zhang Z, Qu X, et al. Roles of STAT3 in leukemia (Review). Int J Oncol, 2018, 53(1): 7-20.
33. Stevens AM, Ruiz MJ, Gerbing RB, et al. Ligand-induced STAT3 signaling increases at relapse and is associated with outcome in pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Haematologica, 2015, 100(12): e496-e500.
34. 赵培伟, 乐鑫, 熊昊, 等. STAT3 基因与儿童急性淋巴细胞白血病的相关性. 中华实用儿科临床杂志, 2016, 31(15): 1152-1155.
35. 贾祝霞, 卢绪章, 蔡晓辉, 等. STAT3 磷酸化介导白血病细胞对多柔比星耐药的机制研究. 中华血液学杂志, 2020, 41(1): 69-71.
36. Smith MR, Satter LRF, Vargas-Hernández A. STAT5b: a master regulator of key biological pathways. Front Immunol, 2022, 13: 1025373.
37. Arfeuille C, Vial Y, Cadenet M, et al. Germline bi-allelic SH2B3/LNK alteration predisposes to a neonatal juvenile myelomonocytic leukemia-like disorder. Haematologica, 2024, 109(8): 2542-2554.
38. Morris R, Butler L, Perkins A, et al. The role of LNK (SH2B3) in the regulation of JAK-STAT signalling in haematopoiesis. Pharmaceuticals (Basel), 2021, 15(1): 24.
39. Lundin Ström KB, Biloglav A, Castor A, et al. Acquired uniparental isodisomies involving chromosome 12 in paediatric B‐cell precursor acute lymphoblastic leukaemia: associations with chromosome 21 gains and SH2B3 mutations. Br J Haematol, 2023, 201(3): 585-588.
40. 陈烈欢, 程龙庆, 彭翔, 等. SH2B1 沉默对胃癌 SGC-7901 细胞增殖、凋亡及 PI3K/AKT 通路的影响. 检验医学与临床, 2020, 17(3): 354-357, 362.
41. Perez-Garcia A, Ambesi-Impiombato A, Hadler M, et al. Genetic loss of SH2B3 in acute lymphoblastic leukemia. Blood, 2013, 122(14): 2425-2432.
42. 吴柳松, 韩春生, 谭梅, 等. LNK 基因单核苷酸多态性与急性白血病易感性研究. 中国实验血液学杂志, 2016, 24(5): 1305-1311.
43. 罗茜, 谭梅, 吴柳松, 等. LNK 基因在急性白血病患者中的表达及临床意义. 中国实验血液学杂志, 2018, 26(2): 317-323.

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