Musashi Proteins as Prognostic Biomarkers: Role in Leukemic Cancer and Stem Cells Growth
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207-216
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May 1, 2025
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10.58578/ajbmbr.v2i2.5581
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Authors:
Muhammad Haris Baig1, Isaac John Umaru2 
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Abstract
Leukemia stem cell's (LSC) ability to self-renew and survive depends on the RNA-binding regulators known as Musashi proteins (MSI1 and MSI2). By stabilizing the mRNAs of key oncogenes like HOXA9 and MYC, MSI2 encourages leukemia growth and treatment resistance, especially in acute myeloid leukemia (AML). On the other hand, MSI1 enhances Notch1 signaling, which helps explain the traits of cancer stem cells in leukemia and solid tumors. Since dysregulation of these proteins is linked to recurrence, treatment resistance, and poor prognosis, they are crucial therapeutic targets. Preclinical research indicates that treatments targeting MSI proteins have potential results. Small-molecule inhibitors and RNA-based methods are being developed to disrupt MSI RNA connections, lowering LSC self-renewal and enhancing chemotherapeutic responses. Inhibiting MSI2 can reduce key pathways such as β-catenin and STAT3, improving therapeutic success in AML. CRISPR-Cas9 technology has also shown promise in overcoming therapeutic resistance by deactivating MSI2.
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Musashi Proteins (MSI1/MSI2); Leukemia Stem Cells (LSCs); Therapeutic Targeting; Chemotherapy Resistance
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Baig, M. H., & Umaru, I. J. (2025). Musashi Proteins as Prognostic Biomarkers: Role in Leukemic Cancer and Stem Cells Growth. African Journal of Biochemistry and Molecular Biology Research, 2(2), 207-216. https://doi.org/10.58578/ajbmbr.v2i2.5581
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
References
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9. Liu, Y., et al., A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy. Cancer Commun (Lond), 2024. 44(3): p. 438-442.
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17. Braune, E.B., A. Seshire, and U. Lendahl, Notch and Wnt Dysregulation and Its Relevance for Breast Cancer and Tumor Initiation. Biomedicines, 2018. 6(4).
18. Azizidoost, S., et al., Signaling pathways governing the behaviors of leukemia stem cells. Genes & Diseases, 2024. 11(2): p. 830-846.
19. Vu, L.P., et al., Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nat Genet, 2017. 49(6): p. 866-875.
20. Palucka, A.K., et al., Acute lymphoblastic leukemias from relapse engraft more rapidly in SCID mice. Leukemia, 1996. 10(3): p. 558-63.
21. Byers, R.J., et al., MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood, 2011. 118(10): p. 2857-67.
22. Huang, F.L., et al., Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. Oncol Lett, 2020. 20(1): p. 448-454.
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29. Mohammed, M.K., et al., Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes & Diseases, 2016. 3(1): p. 11-40.
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32. Taggart, J., et al., MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. Nat Commun, 2016. 7: p. 10739.
33. Redell, M.S., et al., Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood, 2011. 117(21): p. 5701-9.
34. Carnevale, J., et al., SYK regulates mTOR signaling in AML. Leukemia, 2013. 27(11): p. 2118-28.
35. Rattigan, K.M., M.M. Zarou, and G.V. Helgason, Metabolism in stem cell-driven leukemia: parallels between hematopoiesis and immunity. Blood, 2023. 141(21): p. 2553-2565.
36. Huang, L., et al., MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression. Cancer Cell International, 2024. 24(1): p. 273.
37. Teachey, D.T., S.A. Grupp, and V.I. Brown, Mammalian target of rapamycin inhibitors and their potential role in therapy in leukemia and other hematological malignancies. Br J Haematol, 2009. 145(5): p. 569-80.
38. Wang, Y.T., et al., Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines. IUBMB Life, 2020. 72(10): p. 2146-2153.
39. Minuesa, G., et al., Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia. Nat Commun, 2019. 10(1): p. 2691.
40. Forouzanfar, M., et al., Intracellular functions of RNA-binding protein, Musashi1, in stem and cancer cells. Stem Cell Res Ther, 2020. 11(1): p. 193.
41. Löblein, M.T., et al., Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells. Int J Mol Sci, 2021. 22(21).
42. Liu, G.H., et al., Small molecule inhibitors targeting the cancers. MedComm (2020), 2022. 3(4): p. e181.
43. Assis, A.J.B., et al., Therapeutic applications of CRISPR/Cas9 mediated targeted gene editing in acute lymphoblastic leukemia: current perspectives, future challenges, and clinical implications. Front Pharmacol, 2023. 14: p. 1322937.
44. Niv, E., et al., Microsatellite instability in patients with chronic B-cell lymphocytic leukemia. Br J Cancer, 2005. 92(8): p. 1517-23.
45. Chang, L., et al., Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Appl Immunohistochem Mol Morphol, 2018. 26(2): p. e15-e21.
46. Li, X.Y., et al., Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma. Leukemia, 2023. 37(1): p. 164-177.
47. Salvaris, R. and P.L. Fedele, Targeted Therapy in Acute Lymphoblastic Leukaemia. J Pers Med, 2021. 11(8).
48. Hayami, Y., et al., Microsatellite instability as a potential marker for poor prognosis in adult T cell leukemia/lymphoma. Leuk Lymphoma, 1999. 32(3-4): p. 345-9.
49. Zhang, J., Y. Gu, and B. Chen, Mechanisms of drug resistance in acute myeloid leukemia. Onco Targets Ther, 2019. 12: p. 1937-1945.
50. Steeghs, N., J.W. Nortier, and H. Gelderblom, Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol, 2007. 14(2): p. 942-53.
51. Kunze, D., et al., Simultaneous siRNA-mediated knockdown of antiapoptotic BCL2, Bcl-xL, XIAP and survivin in bladder cancer cells. Int J Oncol, 2012. 41(4): p. 1271-7.
52. Kudinov, A.E., et al., Musashi RNA-binding proteins as cancer drivers and novel therapeutic targets. 2017. 23(9): p. 2143-2153.
53. Niu, Y., T. Zhou, and Y.J.F.i.B.-L. Li, Update on the Progress of Musashi-2 in Malignant Tumors. 2025. 30(1): p. 24928.
54. Kharas, M.G. and C.J.J.T.i.c. Lengner, Stem cells, cancer, and MUSASHI in blood and guts. 2017. 3(5): p. 347-356.
55. Zou, D., et al., Down-regulation of Musashi-2 exerts antileukemic effects on acute lymphoblastic leukemia cells and increases sensitivity to dexamethasone. 2024. 103(1): p. 141-151.
56. Evans, C.M., Arginine Methylation of the RNA-Binding Protein MUSASHI2 Regulates Normal and Malignant Blood Fate. 2024, Weill Medical College of Cornell University.
57. Barber, A.G., et al., Regulation of lung cancer initiation and progression by the stem cell determinant Musashi. 2024: p. 2024.04. 11.589053.
2. Matalkah, F., et al., The Musashi proteins direct post-transcriptional control of protein expression and alternate exon splicing in vertebrate photoreceptors. Commun Biol, 2022. 5(1): p. 1011.
3. Kim, M., et al., Publisher Correction: Control of electron-electron interaction in graphene by proximity screening. Nature Communications, 2020. 11(1): p. 3054.
4. Higuchi, M., et al., Paradoxical activation of c-Src as a drug-resistant mechanism. Cell Reports, 2021. 34(12).
5. McKinley, K.L., D. Castillo-Azofeifa, and O.D. Klein, Tools, and Concepts for Interrogating and Defining Cellular Identity. Cell Stem Cell, 2020. 26(5): p. 632-656.
6. Chowdhury, R., A. Sau, and S.M. Musser, Author Correction: Super-resolved 3D tracking of cargo transport through nuclear pore complexes. Nature Cell Biology, 2022. 24(3): p. 400-400.
7. Verstockt, B., M. Parkes, and J.C. Lee, How Do We Predict a Patient’s Disease Course and Whether They Will Respond to Specific Treatments? Gastroenterology, 2022. 162(5): p. 1383-1395.
8. Li, N., et al., The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins. Cell Rep, 2015. 13(11): p. 2440-2455.
9. Liu, Y., et al., A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy. Cancer Commun (Lond), 2024. 44(3): p. 438-442.
10. Barbosa, K. and A.J. Deshpande, Therapeutic targeting of leukemia stem cells in acute myeloid leukemia. Front Oncol, 2023. 13: p. 1204895.
11. Alves, R., et al., Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance. Cancers (Basel), 2021. 13(19).
12. Wang, X., S. Huang, and J.-L. Chen, Understanding of leukemic stem cells and their clinical implications. Molecular Cancer, 2017. 16(1): p. 2.
13. Mojtahedi, H., N. Yazdanpanah, and N. Rezaei, Chronic myeloid leukemia stem cells: targeting therapeutic implications. Stem Cell Res Ther, 2021. 12(1): p. 603.
14. Medicine, N.L.o., National Library of Medicine National Library of Medicine 2024.
15. Magalhães-Gama, F., et al., The Yin-Yang of myeloid cells in the leukemic microenvironment: Immunological role and clinical implications. Front Immunol, 2022. 13: p. 1071188.
16. Harrison, C.J., Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Educ Program, 2013. 2013: p. 118-25.
17. Braune, E.B., A. Seshire, and U. Lendahl, Notch and Wnt Dysregulation and Its Relevance for Breast Cancer and Tumor Initiation. Biomedicines, 2018. 6(4).
18. Azizidoost, S., et al., Signaling pathways governing the behaviors of leukemia stem cells. Genes & Diseases, 2024. 11(2): p. 830-846.
19. Vu, L.P., et al., Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nat Genet, 2017. 49(6): p. 866-875.
20. Palucka, A.K., et al., Acute lymphoblastic leukemias from relapse engraft more rapidly in SCID mice. Leukemia, 1996. 10(3): p. 558-63.
21. Byers, R.J., et al., MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood, 2011. 118(10): p. 2857-67.
22. Huang, F.L., et al., Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. Oncol Lett, 2020. 20(1): p. 448-454.
23. Chen, Y., et al., Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia. Ann Hematol, 2024. 103(4): p. 1211-1220.
24. Joshi, K., et al., Leukemia Stem Cells in the Pathogenesis, Progression, and Treatment of Acute Myeloid Leukemia. Adv Exp Med Biol, 2019. 1143: p. 95-128.
25. Collins, C.T. and J.L. Hess, Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. Oncogene, 2016. 35(9): p. 1090-8.
26. Park, S.M., et al., Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J Clin Invest, 2015. 125(3): p. 1286-98.
27. Ge, Y., et al., miR-30e-5p regulates leukemia stem cell self-renewal through the Cyb561/ROS signaling pathway. Haematologica, 2024. 109(2): p. 411-421.
28. Schmidt, M., et al., Molecular evaluation and vector integration analysis of HCC complicating AAV gene therapy for hemophilia B. Blood Advances, 2023. 7(17): p. 4966-4969.
29. Mohammed, M.K., et al., Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes & Diseases, 2016. 3(1): p. 11-40.
30. Kwon, C., et al., Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol, 2011. 13(10): p. 1244-51.
31. Liu, N., J. Zhang, and C. Ji, The emerging roles of Notch signaling in leukemia and stem cells. Biomark Res, 2013. 1(1): p. 23.
32. Taggart, J., et al., MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. Nat Commun, 2016. 7: p. 10739.
33. Redell, M.S., et al., Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood, 2011. 117(21): p. 5701-9.
34. Carnevale, J., et al., SYK regulates mTOR signaling in AML. Leukemia, 2013. 27(11): p. 2118-28.
35. Rattigan, K.M., M.M. Zarou, and G.V. Helgason, Metabolism in stem cell-driven leukemia: parallels between hematopoiesis and immunity. Blood, 2023. 141(21): p. 2553-2565.
36. Huang, L., et al., MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression. Cancer Cell International, 2024. 24(1): p. 273.
37. Teachey, D.T., S.A. Grupp, and V.I. Brown, Mammalian target of rapamycin inhibitors and their potential role in therapy in leukemia and other hematological malignancies. Br J Haematol, 2009. 145(5): p. 569-80.
38. Wang, Y.T., et al., Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines. IUBMB Life, 2020. 72(10): p. 2146-2153.
39. Minuesa, G., et al., Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia. Nat Commun, 2019. 10(1): p. 2691.
40. Forouzanfar, M., et al., Intracellular functions of RNA-binding protein, Musashi1, in stem and cancer cells. Stem Cell Res Ther, 2020. 11(1): p. 193.
41. Löblein, M.T., et al., Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells. Int J Mol Sci, 2021. 22(21).
42. Liu, G.H., et al., Small molecule inhibitors targeting the cancers. MedComm (2020), 2022. 3(4): p. e181.
43. Assis, A.J.B., et al., Therapeutic applications of CRISPR/Cas9 mediated targeted gene editing in acute lymphoblastic leukemia: current perspectives, future challenges, and clinical implications. Front Pharmacol, 2023. 14: p. 1322937.
44. Niv, E., et al., Microsatellite instability in patients with chronic B-cell lymphocytic leukemia. Br J Cancer, 2005. 92(8): p. 1517-23.
45. Chang, L., et al., Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Appl Immunohistochem Mol Morphol, 2018. 26(2): p. e15-e21.
46. Li, X.Y., et al., Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B-cell lymphoma. Leukemia, 2023. 37(1): p. 164-177.
47. Salvaris, R. and P.L. Fedele, Targeted Therapy in Acute Lymphoblastic Leukaemia. J Pers Med, 2021. 11(8).
48. Hayami, Y., et al., Microsatellite instability as a potential marker for poor prognosis in adult T cell leukemia/lymphoma. Leuk Lymphoma, 1999. 32(3-4): p. 345-9.
49. Zhang, J., Y. Gu, and B. Chen, Mechanisms of drug resistance in acute myeloid leukemia. Onco Targets Ther, 2019. 12: p. 1937-1945.
50. Steeghs, N., J.W. Nortier, and H. Gelderblom, Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol, 2007. 14(2): p. 942-53.
51. Kunze, D., et al., Simultaneous siRNA-mediated knockdown of antiapoptotic BCL2, Bcl-xL, XIAP and survivin in bladder cancer cells. Int J Oncol, 2012. 41(4): p. 1271-7.
52. Kudinov, A.E., et al., Musashi RNA-binding proteins as cancer drivers and novel therapeutic targets. 2017. 23(9): p. 2143-2153.
53. Niu, Y., T. Zhou, and Y.J.F.i.B.-L. Li, Update on the Progress of Musashi-2 in Malignant Tumors. 2025. 30(1): p. 24928.
54. Kharas, M.G. and C.J.J.T.i.c. Lengner, Stem cells, cancer, and MUSASHI in blood and guts. 2017. 3(5): p. 347-356.
55. Zou, D., et al., Down-regulation of Musashi-2 exerts antileukemic effects on acute lymphoblastic leukemia cells and increases sensitivity to dexamethasone. 2024. 103(1): p. 141-151.
56. Evans, C.M., Arginine Methylation of the RNA-Binding Protein MUSASHI2 Regulates Normal and Malignant Blood Fate. 2024, Weill Medical College of Cornell University.
57. Barber, A.G., et al., Regulation of lung cancer initiation and progression by the stem cell determinant Musashi. 2024: p. 2024.04. 11.589053.