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Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia

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Abstract

Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13–1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.

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References

  1. Argiropoulos B, Humphries RK (2007) Hox genes in hematopoiesis and leukemogenesis. Oncogene 26(47):6766–6776

    Article  PubMed  CAS  Google Scholar 

  2. Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F, Park G, Hamwi I, Palmqvist L, Lai CK, Leung M, Lin G, Chaturvedi A, Thakur BK, Iwasaki M, Bilenky M, Thiessen N, Robertson G, Hirst M, Kent D, Wilson NK, Gottgens B, Eaves C, Cleary ML, Marra M, Ganser A, Humphries RK (2011) Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex. Cancer Cell 20(1):39–52

    Article  PubMed  CAS  Google Scholar 

  3. Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, Morgan K, Tam W, Paktinat M, Okabe R, Gozo M, Einhorn W, Lane SW, Scholl C, Frohling S, Fleming M, Ebert BL, Gilliland DG, Jaenisch R, Daley GQ (2010) Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 16(8):903–908

    Article  PubMed  CAS  Google Scholar 

  4. Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, Zhao C, Lagoo A, Gerrard G, Foroni L, Goldman J, Goh H, Kim SH, Kim DW, Chuah C, Oehler VG, Radich JP, Jordan CT, Reya T (2010) Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466(7307):765–768

    Article  PubMed  CAS  Google Scholar 

  5. Byers RJ, Currie T, Tholouli E, Rodig SJ, Kutok JL (2011) MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood 118(10):2857–2867

    Article  PubMed  CAS  Google Scholar 

  6. Mitelman F (1995) ISCN (1995): an International System for Human Cytogenetic Nomenclature. Karger, Basel

    Google Scholar 

  7. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22(4):624–633

    Article  PubMed  Google Scholar 

  8. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, Dohner H, Dohner K (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100(13):4372–4380

    Article  PubMed  CAS  Google Scholar 

  9. Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, Groner S, Spath D, Krauter J, Ganser A, Dohner H, Fischer T, Dohner K (2009) Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 114(12):2386–2392

    Article  PubMed  CAS  Google Scholar 

  10. Wagner K, Damm F, Gohring G, Gorlich K, Heuser M, Schafer I, Ottmann O, Lubbert M, Heit W, Kanz L, Schlimok G, Raghavachar AA, Fiedler W, Kirchner HH, Brugger W, Zucknick M, Schlegelberger B, Heil G, Ganser A, Krauter J (2010) Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor. J Clin Oncol 28(14):2356–2364

    Article  PubMed  CAS  Google Scholar 

  11. Thol F, Damm F, Wagner K, Gohring G, Schlegelberger B, Hoelzer D, Lubbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, Heil G, Heuser M, Krauter J, Ganser A (2010) Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood 116(4):614–616

    Article  PubMed  CAS  Google Scholar 

  12. Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M, Yun H, Göhring G, Schlegelberger B, Hoelzer D, Lübbert M, Kanz L, Fiedler W, Kirchner H, Heil G, Krauter J, Ganser A, Heuser M (2011) Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29(21):2889–2896

    Article  PubMed  CAS  Google Scholar 

  13. Dohner K, Tobis K, Ulrich R, Frohling S, Benner A, Schlenk RF, Dohner H (2002) Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 20(15):3254–3261

    Article  PubMed  Google Scholar 

  14. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A, Bullinger L, Frohling S, Dohner H (2005) Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 106(12):3740–3746

    Article  PubMed  Google Scholar 

  15. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L, Habdank M, Spath D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Dohner H (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358(18):1909–1918

    Article  PubMed  CAS  Google Scholar 

  16. Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, Gohring G, Schlegelberger B, Dohner K, Ottmann O, Lubbert M, Heit W, Kanz L, Schlimok G, Raghavachar A, Fiedler W, Kirchner H, Dohner H, Heil G, Ganser A, Krauter J (2010) Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol 28(4):578–585

    Article  PubMed  CAS  Google Scholar 

  17. Langer C, Marcucci G, Holland KB, Radmacher MD, Maharry K, Paschka P, Whitman SP, Mrozek K, Baldus CD, Vij R, Powell BL, Carroll AJ, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD (2009) Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 27(19):3198–3204

    Article  PubMed  CAS  Google Scholar 

  18. Baldus CD, Martus P, Burmeister T, Schwartz S, Gokbuget N, Bloomfield CD, Hoelzer D, Thiel E, Hofmann WK (2007) Low ERG and BAALC expression identifies a new subgroup of adult acute T-lymphoblastic leukemia with a highly favorable outcome. J Clin Oncol 25(24):3739–3745

    Article  PubMed  CAS  Google Scholar 

  19. Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, Mrozek K, Baldus CD, Carroll AJ, Powell BL, Kolitz JE, Larson RA, Bloomfield CD (2007) High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 25(22):3337–3343

    Article  PubMed  CAS  Google Scholar 

  20. Damm F, Oberacker T, Thol F, Surdziel E, Wagner K, Chaturvedi A, Morgan M, Bomm K, Gohring G, Lubbert M, Kanz L, Fiedler W, Schlegelberger B, Heil G, Schlenk RF, Dohner K, Dohner H, Krauter J, Ganser A, Heuser M (2011) Prognostic importance of histone methyltransferase MLL5 expression in acute myeloid leukemia. J Clin Oncol 29(6):682–689

    Article  PubMed  CAS  Google Scholar 

  21. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, van Putten WL, Valk PJ, van der Poel-van de Luytgaarde S, Hack R, Slater R, Smit EM, Beverloo HB, Verhoef G, Verdonck LF, Ossenkoppele GJ, Sonneveld P, de Greef GE, Lowenberg B, Delwel R (2003) High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients. Blood 101(3):837–845

    Article  PubMed  Google Scholar 

  22. Heuser M, Argiropoulos B, Kuchenbauer F, Yung E, Piper J, Fung S, Schlenk RF, Dohner K, Hinrichsen T, Rudolph C, Schambach A, Baum C, Schlegelberger B, Dohner H, Ganser A, Humphries RK (2007) MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 110(5):1639–1647

    Article  PubMed  CAS  Google Scholar 

  23. Damm F, Heuser M, Morgan M, Wagner K, Gorlich K, Grosshennig A, Hamwi I, Thol F, Surdziel E, Fiedler W, Lubbert M, Kanz L, Reuter C, Heil G, Delwel R, Lowenberg B, Valk PJ, Krauter J, Ganser A (2011) Integrative prognostic risk score in acute myeloid leukemia with normal karyotype. Blood 117(17):4561–4568

    Article  PubMed  CAS  Google Scholar 

  24. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21(24):4642–4649

    Article  PubMed  Google Scholar 

  25. Korn EL (1986) Censoring distributions as a measure of follow-up in survival analysis. Stat Med 5(3):255–260

    Article  PubMed  CAS  Google Scholar 

  26. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 92(7):2322–2333

    PubMed  CAS  Google Scholar 

  27. Nakano A, Kanemura Y, Mori K, Kodama E, Yamamoto A, Sakamoto H, Nakamura Y, Okano H, Yamasaki M, Arita N (2007) Expression of the neural RNA-binding protein Musashi1 in pediatric brain tumors. Pediatr Neurosurg 43(4):279–284

    Article  PubMed  Google Scholar 

  28. Wang XY, Yin Y, Yuan H, Sakamaki T, Okano H, Glazer RI (2008) Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways. Mol Cell Biol 28(11):3589–3599

    Article  PubMed  CAS  Google Scholar 

  29. Sureban SM, May R, George RJ, Dieckgraefe BK, McLeod HL, Ramalingam S, Bishnupuri KS, Natarajan G, Anant S, Houchen CW (2008) Knockdown of RNA binding protein musashi-1 leads to tumor regression in vivo. Gastroenterology 134(5):1448–1458

    Article  PubMed  CAS  Google Scholar 

  30. Garzon R, Garofalo M, Martelli MP, Briesewitz R, Wang L, Fernandez-Cymering C, Volinia S, Liu CG, Schnittger S, Haferlach T, Liso A, Diverio D, Mancini M, Meloni G, Foa R, Martelli MF, Mecucci C, Croce CM, Falini B (2008) Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A 105(10):3945–3950

    Article  PubMed  CAS  Google Scholar 

  31. Mullighan CG, Kennedy A, Zhou X, Radtke I, Phillips LA, Shurtleff SA, Downing JR (2007) Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21(9):2000–2009

    Article  PubMed  CAS  Google Scholar 

  32. Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, Uitterlinden AG, Erpelinck CA, Delwel R, Lowenberg B, Valk PJ (2005) Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106(12):3747–3754

    Article  PubMed  CAS  Google Scholar 

  33. Yassin ER, Sarma NJ, Abdul-Nabi AM, Dombrowski J, Han Y, Takeda A, Yaseen NR (2009) Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9. PLoS One 4(8):e6719

    Article  PubMed  Google Scholar 

  34. Battelli C, Nikopoulos GN, Mitchell JG, Verdi JM (2006) The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1. Mol Cell Neurosci 31(1):85–96

    Article  PubMed  CAS  Google Scholar 

  35. Imai T, Tokunaga A, Yoshida T, Hashimoto M, Mikoshiba K, Weinmaster G, Nakafuku M, Okano H (2001) The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol Cell Biol 21(12):3888–3900

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We are indebted to all patients and contributing doctors. We thank Kerstin Görlich, Martin Wichmann, Elvira Lux, and Sylvia Horter for their excellent support. We thank Prof. R. Blasczyk for the supply of healthy control samples. This study was supported by the Deutsche Krebshilfe e.V (grant no. 109003), grant no. DJCLS R 10/22 from the Deutsche-José-Carreras Leukämie-Stiftung e.V, grant no. M 47.1 from the H. W. & J. Hector Stiftung, the Dieter-Schlag-Stiftung grant 2011, German Federal Ministry of Education and research grant number 01EO0802, DFG grant HE 5240/4-1 and TH 1779/1-1, and HiLF grant from Hannover Medical School awarded to FT.

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The authors indicated no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Felicitas Thol, Claudia Winschel, Ann-Kathrin Sonntag, Frederik Damm, Katharina Wagner, Anuhar Chaturvedi, Jürgen Krauter, Arnold Ganser & Michael Heuser

  2. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    Gudrun Göhring & Brigitte Schlegelberger

  3. Department of Hematology-Oncology, University of Freiburg Medical Center, Freiburg, Germany

    Michael Lübbert

  4. Department of Medicine II, Oncological Center, Hubertus Wald University Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Walter Fiedler

  5. Department of Internal Medicine III, Krankenhaus Siloah, Hannover, Germany

    Hartmut Kirchner

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  1. Felicitas Thol
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  2. Claudia Winschel
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Correspondence to Felicitas Thol.

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Arnold Ganser and Michael Heuser have shared senior authorship.

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Thol, F., Winschel, C., Sonntag, AK. et al. Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia. Ann Hematol 92, 315–323 (2013). https://doi.org/10.1007/s00277-012-1637-5

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  • DOI: https://doi.org/10.1007/s00277-012-1637-5

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