Signaling pathways involved in chronic myeloid leukemia pathogenesis: the importance of targeting Musashi2-Numb signaling to eradicate leukemia stem cells

Document Type: Review Article


1 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

2 Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

4 Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

5 Department of Hematology, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran


Objective(s): Chronic myeloid leukemia (CML) is a myeloid clonal proliferation disease defining by the presence of the Philadelphia chromosome that shows the movement of BCR-ABL1. In this study, the critical role of the Musashi2-Numb axis in determining cell fate and relationship of the axis to important signaling pathways such as Hedgehog and Notch that are essential for self-renewal pathways in CML stem cells will be reviewed meticulously.
Materials and Methods: In this review, a PubMed search using the keywords of Leukemia, signaling pathways, Musashi2-Numb was performed, and then we summarized different research works.
Results: Although tyrosine kinase inhibitors such as Imatinib significantly kill and remove the cell with BCR-ABL1 translocation, they are unable to target BCR-ABL1 leukemia stem cells. The main problem is stem cells resistance to Imatinib therapy. Therefore, the identification and control of downstream molecules/ signaling route of the BCR-ABL1 that are involved in the survival and self-renewal of leukemia stem cells can be an effective treatment strategy to eliminate leukemia stem cells, which supposed to be cured by Musashi2-Numb signaling pathway.
Conclusion: The control of molecules /pathways downstream of the BCR-ABL1 and targeting Musashi2-Numb can be an effective therapeutic strategy for treatment of chronic leukemia stem cells. While Musashi2 is a poor prognostic marker in leukemia, in treatment and strategy, it has significant diagnostic value.


Main Subjects

1. Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson genetics in medicine e-book. Elsevier Health Sciences 2015.

2. Sharpless NE, DePinho RA. Cancer biology: gone but not forgotten. Nature 2007; 445:606-607.

3. Taylor J, Xiao W, Abdel-Wahab O. Diagnosis and classification of hematologic malignancies on the basis of genetics. Blood 2017; 130:410-423.

4. Toro-Tobón D, Agosto S, Ahmadi S, Koops M, Bruder JM. Chronic myeloid leukemia associated hypercalcemia: a case report and literature review. Am J Case Rep 2017; 18:203-207.

5. Sultan S, Zaheer HA, Irfan SM, Ashar S. Acute myeloid leukemia: clinical spectrum of 125 patients. Asian Pac J Cancer Prev 2016; 17:369-379.

6. Keating GM. Dasatinib: a review in chronic myeloid leukaemia and pH+ acute lymphoblastic leukaemia. Drugs 2017; 77:85-96.

7. Babashah S, Rezaei-Tavirani M, Zamanian-Azodi M, Saki N. Chronic myeloid leukemia as a stem cell-derived malignancy. J Paramed Sci 2012; 3:43-55.

8. Maru Y. Molecular biology of chronic myeloid leukemia. Cancer Sci 2012; 103:1601-1610.

9. Sawyers CL. Even better kinase inhibitors for chronic myeloid leukemia. N Engl J Med 2010; 362:2314-2315.

10. Hantschel O, Superti-Furga G. Regulation of the c-Abl and Bcr–Abl tyrosine kinases. Nat Rev Mol Cell Biol 2004; 5:33-44.

11. Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang Y, et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 1999; 399:814-817.

12. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the philadelphia chromosome. N Engl J Med 2001; 344:1038-1042.

13. Calabretta B, Perrotti D. The biology of CML blast crisis. Blood 2004; 103:4010-4022.

14. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring. Am J Hematol 2016; 91:252-265.

15. Quintás-Cardama A, Cortes JE. Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 2006; 973:81-88.

16. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Kriener S, Engels K, Staib P, et al. Effects of the tyrosine kinase inhibitor imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia. Histol Histopathol 2004; 19:1277-1288.

17. Priyanka A, Mrinal M. The role of new tyrosine kinase inhibitors in chronic myeloid leukemia. Cancer J 2016; 22:40–50.

18. Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Crit Rev Oncol Hematol 2006; 57:145-164.

19. Paul MK, Mukhopadhyay AK. Tyrosine kinase - role and significance in cancer. Int J Med Sci 2004; 1:101-115.

20. Castagnetti F, Gugliotta G, Breccia M, Iurlo A, Levato L, Albano F, et al. The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol 2017; 92:797-805.

21. Huang R, Kang Q, Liu H, Li Y. New insights into the molecular resistance mechanisms of chronic myeloid leukemia. Curr Cancer Drug Targets 2016; 16:323-345.

22. Chen Y, Peng C, Sullivan C, Li D, Li S. Critical molecular pathways in cancer stem cells of chronic myeloid leukemia. Leukemia 2010; 24:1545-1554.

23. Perrotti D, Silvestri G, Stramucci L, Yu J, Trotta R. Cellular and molecular networks in chronic myeloid leukemia: the leukemic stem, progenitor and stromal cell interplay. Curr drug targets 2017; 18:377-388.

24. Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004; 6:587-596.

25. Heidel FH, Mar BG, Armstrong SA. Self-renewal related signaling in myeloid leukemia stem cells. Int J Hematol 2011; 94:109-117.

26. Duman-Scheel M, Weng L, Xin S, Du W. Hedgehog regulates cell growth and proliferation by inducing cyclin D and cyclin E. Nature 2002; 417:299-304.

27. Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 2010; 466:133-137.

28. Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351:657-667.

29. Bertacchini J, Ketabchi N, Mediani L, Capitani S, Marmiroli S, Saki N. Inhibition of Ras-mediated signaling pathways in CML stem cells. Cell Oncol 2015; 38:407-418.

30.Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. EMBO J 2005; 24:170-179.

31.Rådmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci 2007; 32:332-341.

32.Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 2003; 100:6523-6528.

33.Martínez-Gac L, Marqués M, García Z, Campanero MR, Carrera AC. Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead. Mol Cell Biol 2004; 24:2181-2189.

34.Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 2007; 1:101-112.

35.Fasano CA, Dimos JT, Ivanova NB, Lowry N, Lemischka IR, Temple S. shRNA knockdown of Bmi-1 reveals a critical role for p21-Rb pathway in NSC self-renewal during development. Cell Stem Cell 2007; 1:87-99.

36.Reya T, Morrison SJ, MF Clarke, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414:105-111.

37.Nishimoto Y, Okano H. New insight into cancer therapeutics: induction of differentiation by regulating the Musashi/Numb/Notch pathway. Cell Res 2010; 20:1083-1085.

38.Ito T, Kwon HY, Zimdahl B, Congdon KL, Blum J, Lento WE, et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 2010; 466:765-768.

39.Kaeda J, Ringel F, Oberender C, Mills K, Quintarelli C, Pane F, et al. Up-regulated MSI2 is associated with more aggressive chronic myeloid leukemia. Leuk Lymphoma 2015; 56:2105-2113.

40.Bumbea H, Vladareanu AM, Voican I, Cisleanu D, Barsan L, Onisai M. Chronic myeloid leukemia therapy in the era of tyrosine kinase inhibitors-the first molecular targeted treatment. J Med Life 2010; 15:162–166.

41.Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned?. Blood 2011; 117:755-763.

42.Sullivan C, Peng C, Chen Y, Li D, Li S. Targeted therapy of chronic myeloid leukemia. Biochem pharmacol 2010; 80:584-591.

43.Talpaz M, Hehlmann R, Quinta´s-Cardama A, Mercer J, Cortes J. Re-emergence of interferon-a, in the treatment of chronic myeloid leukemia. Leukemia 2013; 27:803–812.

44.Wetzel R, Goss VL, Norris B, Popova L, Melnick M, Smith BL. Evaluation of CML model cell lines and imatinib mesylate response: determinants of signaling profiles. J Immunol Methods 2005; 305:59-66.

45.Kayastha GK, Ranjitkar N, Gurung R, KC R, Karki S, Shrestha R, et al. The use of Imatinib resistance mutation analysis to direct therapy in Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia patients failing Imatinib treatment, in Patan hospital, Nepal. Br J Haematol 2017; 177:1000-1007.

46.Bixby D, Talpaz M. Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia. Leukemia 2011; 25:7-22.

47.Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007; 109:58-60.

48.Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer cell 2008; 14:238-249.

49.Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet oncol 2010; 11:1029-1035.

50.Cortes J, Hochhaus A, Hughes T, Kantarjian H. Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol 2011; 29:524-531.

51.Verga Falzacappa MV, Ronchini C, Reavie LB, Pelicci PG. Regulation of self-renewal in normal and cancer stem cells. FEBS Journal 2012; 279:3559-3572.

52.Dick D. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med 1997; 3:730-737.

53.Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL, et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005; 105:2093-2098.

54.Graham SM, Vass JK, Holyoake TL, Graham GJ. Transcriptional analysis of quiescent and proliferating CD34+ human hemopoietic cells from normal and chronic myeloid leukemia sources. Stem Cells 2007; 25:3111-3120.

55.Graham SM, Jørgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99:319-325.

56.Jørgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007; 109:4016-4019.

57.Houghton J, Morozov A, Smirnova I, Wang TC. Stem cells and cancers. Seminars in cancer biology. Elsevier 2007; 191-203.

58.Horne GA, Jackson L, Helgason V, Holyoake TL. Stem Cell Guardians–Old and New Perspectives in LSC Biology. Curr drug targets 2017; 18:405-413.

59.Naka K, Hoshii T, Hirao A. Novel therapeutic approach to eradicate tyrosine kinase inhibitor resistant chronic myeloid leukemia stem cells. Cancer Sci 2010; 101:1577-1581.

60.Park CY, Tseng D, Weissman IL. Cancer stem cell–directed therapies: recent data from the laboratory and clinic. Mol Ther 2009; 17:219-230.

61.Huntly BJ, Gilliland DG. Leukemia stem cells and the evolution of cancer-stem-cell research. Nature Reviews Cancer 2005; 5:311-321.

62.Krause DS, Van Etten RA. Right on target: eradicating leukemic stem cells. Trends Mol Med 2007; 13:470-481.

63.Jamieson CH. Chronic myeloid leukemia stem cells. ASH Education Program Book 2008; 436-442.

64.Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, et al. Stem cell–related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 2008; 26:3015-3024.

65. Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells. Oncogene 2004; 23:7274-7282.

66. Lobo NA, Shimono Y, Qian D, Clarke MF. The biology of cancer stem cells. Annu Rev Cell Dev Biol 2007; 23:675-699

67. Tan BT, Park CY, Ailles LE, Weissman IL. The cancer stem cell hypothesis: a work in progress. Laboratory Investigation 2006; 86:1203-1207.

68. Zhang H, Li S. Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells. Protein Cell 2013; 4:186-196.

69.Chavez-Gonzalez A, Bakhshinejad B, Pakravan K, Guzman ML, Babashah S. Novel strategies for targeting leukemia stem cells: sounding the death knell for blood cancer. Cell Oncol 2017; 40:1-20.

70.Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nature med 2010; 16:903-908.

71.Sakakibara SI, Nakamura Y, Satoh H, Okano H. RNA-binding protein Musashi2: developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS. J Neurosci 2001; 21:8091-8107.

72.RG de Bruin. TJ Rabelink. AJ van Zonneveld. EP van der Veer. Emerging roles for RNA-binding proteins as effectors and regulators. Eur Heart J 2017; 38:1380-1388.

73.Zhang H, Tan S, Wang J, Chen S, Quan J, Xian J, et al. Musashi2 modulates K562 leukemic cell proliferation and apoptosis involving the MAPK pathway. Exp Cell Res 2014; 320:119-127.

74.Okano H, Kawahara H, Toriya M, Nakao K, Shibata S, Imai T. Function of RNA-binding protein Musashi-1 in stem cells. Exp Cell Res 2005; 306:349-356.

75.Sugiyama-Nakagiri Y, Akiyama M, Shibata S, Okano H, Shimizu H. Expression of RNA-binding protein Musashi in hair follicle development and hair cycle progression. Am J Pathol 2006; 168:80-92.

76.Sakakibara S, Nakamura Y, Yoshida T, Shibata S, Koike M, Takano H, et al. RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc Natl Acad Sci USA 2002; 99:15194-15199.

77.Sakakibara S, Imai T, Hamaguchi K, Okabe M, Aruga J, Nakajima K, et al. Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 1996; 176:230-242.

78.Sakakibara S, Okano H. Expression of neural RNA-binding proteins in the postnatal CNS: implications of their roles in neuronal and glial cell development. J Neurosci 1997; 17:8300-8312.

79.Akasaka Y, Saikawa Y, Fujita K, Kubota T, Ishikawa Y, Fujimoto A, et al. Expression of a candidate marker for progenitor cells, Musashi-1, in the proliferative regions of human antrum and its decreased expression in intestinal metaplasia. Histopathology 2005; 47:348-356.

80.Kayahara T, Sawada M, Takaishi S, Fukui H, Seno H, Fukuzawa H, et al. Candidate markers for stem and early progenitor cells, Musashi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS letters 2003; 535:131-135.

81.Potten CS, Booth C, Tudor GL, Booth D, Brady G, Hurley P, et al. Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation 2003; 71:28-41.

82.Clarke RB, Spence K, Anderson E, Howell A, Okano H, Potten CS. A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol 2005; 277:443-456.

83.Li D, Peng X, Yan D, Tang H, Huang F, Yang Y, et al. Msi-1 is a predictor of survival and a novel therapeutic target in colon cancer. Ann Surg Oncol 2011; 18:2074-2083.

84.Wang XY, Penalva LO, Yuan H, Linnoila RI, Lu J, Okano H, et al. Musashi1 regulates breast tumor cell proliferation and is a prognostic indicator of poor survival. Mol Cancer 2010; 221:3-12.

85.Nakano A, Kanemura Y, Mori K, Kodama E, Yamamoto A, Sakamoto H, et al. Expression of the Neural RNA-binding protein Musashi1 in pediatric brain tumors. Pediatr Neurosurg 2007; 43:279-284.

86.Nikpour P, Baygi ME, Steinhoff C, Hader C, Luca AC, Mowla SJ, et al. The RNA binding protein Musashi1 regulates apoptosis, gene expression and stress granule formation in urothelial carcinoma cells. J Cell Mol Med 2011; 15:1210-1224.

87.Kanemura Y, Yamasaki M, Mori K, Fujikawa H, Hayashi H, Nakano A, et al. Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. Differentiation 2001; 68:141-152.

88.Bobryshev Y, Freeman A, Botelho N, Tran D, Levert-Mignon A, Lord R. Expression of the putative stem cell marker Musashi-1 in Barrett’s esophagus and esophageal adenocarcinoma. Dis Esophagus 2010; 23:580-589.

89.Ye F, Zhou C, Cheng Q, Shen J, Chen H. Stem-cell-abundant proteins Nanog, Nucleostemin and Musashi1 are highly expressed in malignant cervical epithelial cells. BMC Cancer 2008; 8:108.

90.Toda M, Iizuka Y, Yu W, Imai T, Ikeda E, Yoshida K, et al. Expression of the neural RNA-binding protein Musashi1 in human gliomas. Glia 2001; 34:1-7.

91.Hope KJ, Cellot S, Ting SB, MacRae T, Mayotte N, Iscove NN, et al. An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity. Cell Stem Cell 2010; 7:101-113.

92.Sureban SM, May R, George RJ, Dieckgraefe BK, McLeod HL, Ramalingam S, et al. Knockdown of RNA binding protein musashi-1 leads to tumor regression in vivo. Gastroenterology 2008; 134:1448-1458.

93.Moreira AL, Gonen M, Rekhtman N, Downey RJ. Progenitor stem cell marker expression by pulmonary carcinomas. Mod Pathol 2010; 23:889-895. Andrés-Aguayo L, Varas F, Graf T. Musashi 2 in hematopoiesis. Curr Opin hematol 2012; 19:268-272.

95.Moore MA. A cancer fate in the hands of a samurai. Nature medicine 2010; 16:963-965.

96.MacNicol AM, Wilczynska A, MacNicol MC. Function and regulation of the mammalian Musashi mRNA translational regulator. Biochem Soc Trans 2008; 36:528-530.

97.Cohen MM. The hedgehog signaling network. Am Journal Med Genet A 2003; 123:5-28.

98.Lewis MT, Veltmaat JM. Next stop, the twilight zone: hedgehog network regulation of mammary gland development. J Mammary Gland Biol and Neoplasia 2004; 9:165-181.

99.Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15:3059-3087.

100.Yang L, Xie G, Fan Q, Xie J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 2010; 29:469-481.

101.Varjosalo M, Taipale J. Hedgehog signaling. J Cell Sci 2007; 120:3-6.

102.Nehmé R, Mus-Veteau I. Proteins of the Hedgehog signaling pathway as therapeutic targets against cancer. Expert Rev Proteomics 2010; 7:601-612.

103.Babashah S, Sadeghizadeh M, Hajifathali A, Tavirani MR, Zomorod MS, Ghadiani M, et al. Targeting of the signal transducer Smo links microRNA-326 to the oncogenic Hedgehog pathway in CD34+ CML stem/progenitor cells. International Journal of Cancer 2013; 133:579-589.

104.Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature 2009; 458:776-779.

105.Hambardzumyan D, Becher OJ, Holland EC. Cancer stem cells and survival pathways. Cell Cycle 2008; 7:1371-1378.

106.Imai T, Tokunaga A, Yoshida T, Hashimoto M, Mikoshiba K, Weinmaster G, et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Molecular and Cellular Biology 2001; 21:3888-3900.

107.Nakahara F, Sakata-Yanagimoto M, Komeno Y, Kato N, Uchida T, Haraguchi K, et al. Hes1 immortalizes committed progenitors and plays a role in blast crisis transition in chronic myelogenous leukemia. Blood 2010; 115:2872-2881.

108.Byers RJ, Currie T, Tholouli E, Rodig SJ, Kutok JL. MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia. Blood 2011; 118:2857-2867.

109.Scherr M, Battmer K, Blömer U, Schiedlmeier B, Ganser A, Grez M, et al. Lentiviral gene transfer into peripheral blood–derived CD34+ NOD/SCID-repopulating cells. Blood 2002; 99:709-712.