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Molecular Cancer
Published in: Molecular Cancer 1/2007

Open Access 01-12-2007 | Research

Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia

Authors: Pavinder Kaur, Niklas Feldhahn, Bin Zhang, Daniel Trageser, Markus Müschen, Veerle Pertz, John Groffen, Nora Heisterkamp

Published in: Molecular Cancer | Issue 1/2007

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Abstract

Background

Ph-positive leukemias are caused by the aberrant fusion of the BCR and ABL genes. Nilotinib is a selective Bcr/Abl tyrosine kinase inhibitor related to imatinib, which is widely used to treat chronic myelogenous leukemia. Because Ph-positive acute lymphoblastic leukemia only responds transiently to imatinib therapy, we have used mouse models to test the efficacy of nilotinib against lymphoblastic leukemia caused by the P190 form of Bcr/Abl.

Results

After transplant of 10,000 highly malignant leukemic cells into compatible recipients, untreated mice succumbed to leukemia within 21 days, whereas mice treated with 75 mg/kg nilotinib survived significantly longer. We examined cells from mice that developed leukemia while under treatment for Bcr/Abl kinase domain point mutations but these were not detected. In addition, culture of such cells ex vivo showed that they were as sensitive as the parental cell line to nilotinib but that the presence of stromal support allowed resistant cells to grow out. Nilotinib also exhibited impressive anti-leukemia activity in P190 Bcr/Abl transgenic mice that had developed overt leukemia/lymphoma masses and that otherwise would have been expected to die within 7 days. Visible lymphoma masses disappeared within six days of treatment and leukemic cell numbers in peripheral blood were significantly reduced. Treated mice survived more than 30 days.

Conclusion

These results show that nilotinib has very impressive anti-leukemia activity but that lymphoblastic leukemia cells can become unresponsive to it both in vitro and in vivo through mechanisms that appear to be Bcr/Abl independent.
Appendix
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Literature
1.
Faderl S, Jeha S, Kantarjian HM: The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003, 98: 1337-1354. 10.1002/cncr.11664CrossRefPubMed
2.
Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med. 2003, 138: 819-830.CrossRefPubMed
3.
Laurent E, Talpaz M, Kantarjian H, Kurzrock R: The BCR gene and Philadelphia chromosome-positive leukemogenesis. Cancer Res. 2001, 61: 2343-2355.PubMed
4.
Daley GQ, Van Etten RA, Baltimore D: Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990, 247: 824-830. 10.1126/science.2406902CrossRefPubMed
5.
Lugo TG, Pendergast AM, Muller AJ, Witte ON: Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990, 247: 1079-1082. 10.1126/science.2408149CrossRefPubMed
6.
Ren R: Mechanism of BCR-ABL in the pathogenesis of chronic myeloid leukaemia. Nat Rev Cancer. 2005, 5: 172-183. 10.1038/nrc1567CrossRefPubMed
7.
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001, 344. 10.1-1037.CrossRefPubMed
8.
Deininger M, Buchdunger E, Druker BJ: The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005, 105: 2640-2653. 10.1182/blood-2004-08-3097CrossRefPubMed
9.
Druker BJ, O'Brien SG, Cortes J, Radich J: Chronic myelogenous leukemia. Hematology Am Soc Hematol Educ Program. 2002, 111-135.
10.
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA, IRIS Investigators: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006, 355: 2408-2417. 10.1056/NEJMoa062867CrossRefPubMed
11.
Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL: Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001, 293: 876-880. 10.1126/science.1062538CrossRefPubMed
12.
le Coutre P, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C: Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood. 2000, 95: 1758-1766.PubMed
13.
Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, Lange T, Hochhaus A, Wystub S, Bruck P, Hoelzer D, Ottmann OG: Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007 Apr 3,
14.
Ricci C, Scappini B, Divoky V, Gatto S, Onida F, Verstovsek S, Kantarjian HM, Beran M: Mutations in the ATP-binding pocket of the ABL kinase domain in an STI571-resistant BCR/ABL-positive cell line. Cancer Res. 2002, 62: 5995-5998.PubMed
15.
Hofmann WK, Jones LC, Lemp NA, de Vos S, Gschaidmeier H, Hoelzer D, Ottmann OG, Koeffler HPNA: Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood. 2002, 99: 1860-1862. 10.1182/blood.V99.5.1860CrossRefPubMed
16.
Roche-Lestienne C, Soenen-Cornu V, Grardel-Duflos N, La JL, Philippe N, Facon T, Fenaux P, Preudhomme C: Several types of mutations of the Abl gene be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment. Blood. 2002, 100: 1014-1018. 10.1182/blood.V100.3.1014CrossRefPubMed
17.
Gruber FX, Hjorth-Hansen H, Mikkola I, Stenke L, Johansen T: A novel Bcr-Abl splice isoform is associated with the L248V mutation in CML patients with acquired resistance to imatinib. Leukemia. 2006, 20: 2057-2060. 10.1038/sj.leu.2404400CrossRefPubMed
18.
Scappini B, Gatto S, Onida F, Ricci C, Divoky V, Wierda WG, Andreeff M, Dong L, Hayes K, Verstovsek S, Kantarjian HM, Beran M: Changes associated with the development of resistance to imatinib (STI571) in two leukemic cell lines expressing p210 Bcr/Abl protein. Cancer. 2004, 100: 1459-1471. 10.1002/cncr.20131CrossRefPubMed
19.
Hochhaus A: Cytogenetic and molecular mechanisms of resistance to Imatinib. Semin Hematol. 2003, 40: 69-79.CrossRefPubMed
20.
Hochhaus A, Kreil S, Corbin AS, La Rosee P, Mueller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R: Molecular and chromosomal mechanisms of resistance to Imatinib (STI) therapy. Leukemia. 2002, 16: 2190-2196. 10.1038/sj.leu.2402741CrossRefPubMed
21.
Cowan-Jacob SW, Guez V, Fendrich G, Griffin JD, Fabbro D, Furet P, Liebetanz J, Mestan J, Manley PW: Imatinib (STI571) resistance in chronic myelogenous leukemia: molecular basis of the underlying mechanisms and potential strategies for treatment. Mini Rev Med Chem. 2004, 4: 285-299. 10.2174/1389557043487321 10.2174/1389557043487321CrossRefPubMed
22.
Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG: A phase 2 study of Imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemia. Blood. 2002, 100: 1965-1971. 10.1182/blood-2001-12-0181CrossRefPubMed
23.
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M: 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. 10.1056/NEJM200104053441402CrossRefPubMed
24.
Weisberg E, Manley PW, Breitenstein W, Brueggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Mohammed A, Neuberg D, Wright RD, Gilliland DG, Griffin JD: Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005, 7: 129-141. 10.1016/j.ccr.2005.01.007CrossRefPubMed
25.
Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG: Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006, 354: 2542-2551. 10.1056/NEJMoa055104CrossRefPubMed
26.
Verstovsek S, Golemovic M, Kantarjian H, Manshouri T, Estrov Z, Manley P, Sun T, Arlinghaus RB, Alland L, Dugan M, Cortes J, Giles F, Beran M: AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells. Cancer. 2005, 104: 1230-1236. 10.1002/cncr.21299CrossRefPubMed
27.
Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW, Mestan J, Dugan M, Alland L, Griffin JD, Arlinghaus RB, Sun T, Kantarjian H, Beran M: AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res. 2005, 11: 4941-4947. 10.1158/1078-0432.CCR-04-2601CrossRefPubMed
28.
O'Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, Druker BJ: In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005, 65: 4500-4505. 10.1158/0008-5472.CAN-05-0259CrossRefPubMed
29.
Ray A, Cowan-Jacob SW, Manley PW, Mestan J, Griffin JD: Identification of Bcr/Abl point mutations conferring resistance to the Abl kinase inhibitor AMN107 (Nilotinib) by a random mutagenesis study. Blood. 2007 Feb 15,
30.
von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J: Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. 2006, 108: 1328-1333. 10.1182/blood-2005-12-010132CrossRefPubMed
31.
Bradeen HA, Eide CA, O'Hare T, Johnson KJ, Willis SG, Lee FY, Druker BJ, Deininger MW: Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood. 2006, 108: 2332-2338. 10.1182/blood-2006-02-004580PubMedCentralCrossRefPubMed
32.
Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD: AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006, 94: 1765-1769. 10.1038/sj.bjc.6603170PubMedCentralCrossRefPubMed
33.
Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J: Acute leukemia in BCR/ABL transgenic mice. Nature. 1990, 344: 251-254. 10.1038/344251a0CrossRefPubMed
34.
Voncken JW, Griffiths S, Greaves MF, Pattengale PK, Heisterkamp N, Groffen J: Restricted oncogenicity of BCR/ABL p190 in transgenic mice. Cancer Res. 1992, 52: 4534-4539.PubMed
35.
Hardy RR, Li YS, Allman D, Asano M, Gui M, Hayakawa K: B-cell commitment, development and selection. Immunol Rev. 2000, 175: 23-32. 10.1111/j.1600-065X.2000.imr017517.xCrossRefPubMed
36.
Samanta AK, Lin H, Sun T, Kantarjian H, Arlinghaus RB: Janus kinase 2: a critical target in chronic myelogenous leukemia. Cancer Res. 2006, 66: 6468-6472. 10.1158/0008-5472.CAN-06-0025CrossRefPubMed
37.
Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, Hochhaus A, Neubauer A, Burchert A: Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood. 2007, 109: 2147-2155. 10.1182/blood-2006-08-040022CrossRefPubMed
38.
Mishra S, Zhang B, Cunnick JM, Heisterkamp N, Groffen J: Resistance to imatinib of bcr/abl P190 lymphoblastic leukemia cells. Cancer Res. 2006, 66: 5387-5393. 10.1158/0008-5472.CAN-05-3058CrossRefPubMed
39.
Mishra S, Pertz V, Zhang B, Kaur P, Shimada H, Groffen J, Kazimierczuk Z, Pinna LA, Heisterkamp N: Treatment of P190 Bcr/Abl lymphoblastic leukemia cells with inhibitors of the serine/threonine kinase CK2. Leukemia. 2007, 21: 178-180. 10.1038/sj.leu.2404460CrossRefPubMed
40.
Zhang B, Groffen J, Heisterkamp N: Increased resistance to a farnesyltransferase inhibitor by N-cadherin expression in Bcr/Abl-P190 lymphoblastic leukemia cells. Leukemia. 2007, 21: 1189-1197. 10.1038/sj.leu.2404667CrossRefPubMed
41.
Xie S, Wang Y, Liu J, Sun T, Wilson MB, Smithgall TE, Arlinghaus RB: Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene. 2001, 20: 6188-6195. 10.1038/sj.onc.1204834CrossRefPubMed
42.
Xie S, Lin H, Sun T, Arlinghaus RB: Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene. 2002, 21: 7137-7146. 10.1038/sj.onc.1205942CrossRefPubMed
43.
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA: AK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004, 18: 189-218. 10.1038/sj.leu.2403241CrossRefPubMed
44.
Murray PJ: The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007, 178: 2623-2629.CrossRefPubMed
45.
Rane SG, Reddy EP: JAKs, STATs and Src kinases in hematopoiesis. Oncogene. 2002, 21: 3334-3358. 10.1038/sj.onc.1205398CrossRefPubMed
46.
Ihle JN, Gilliland DG: Jak2: normal function and role in hematopoietic disorders. Curr Opin Genet Dev. 2007, 17: 8-14. 10.1016/j.gde.2006.12.009CrossRefPubMed
47.
Zhang XF, Wang JF, Matczak E, Proper JA, Groopman JE: Janus kinase 2 is involved in stromal cell-derived factor-1alpha-induced tyrosine phosphorylation of focal adhesion proteins and migration of hematopoietic progenitor cells. Blood. 2001, 97: 3342-3348. 10.1182/blood.V97.11.3342CrossRefPubMed
48.
Williams RT, Roussel MF, Sherr CJ: Arf gene loss enhances oncogenicity and limits imatinib response in mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2006, 103: 6688-6693. 10.1073/pnas.0602030103PubMedCentralCrossRefPubMed
49.
Mishra S, Zhang B, Groffen J, Heisterkamp N: A farnesyltransferase inhibitor increases survival of mice with very advanced stage acute lymphoblastic leukemia/lymphoma caused by P190 Bcr/Abl. Leukemia. 2004, 18: 23-28. 10.1038/sj.leu.2403203CrossRefPubMed
50.
Zhang B, Groffen J, Heisterkamp N: Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter, ATP11A. Blood. 2005, 106: 1355-1361. 10.1182/blood-2004-09-3655PubMedCentralCrossRefPubMed
51.
Mishra S, Reichert A, Cunnick J, Senadheera D, Hemmeryckx B, Heisterkamp N, Groffen J: Protein Kinase CKIIalpha interacts with the Bcr moiety of Bcr/Abl-expressing cells. Oncogene. 2003, 22: 8255-8262. 10.1038/sj.onc.1207156CrossRefPubMed
52.
Sacha T, Hochhaus A, Hanfstein B, Mueller MC, Rudzki Z, Czopek J, Wolska-Smolen T, Czekalska S, Salamanchuk Z, Jakobczyk M, Skotnicki AB: ABL-Kinase domain point mutation as a cause of Imatinib (STI 571) resistance in CML patient who progress to myeloid blast crisis. Leuk Res. 2003, 27: 1163-1166. 10.1016/S0145-2126(03)00117-6CrossRefPubMed
Metadata
Title
Nilotinib treatment in mouse models of P190 Bcr/Abl lymphoblastic leukemia
Authors
Pavinder Kaur
Niklas Feldhahn
Bin Zhang
Daniel Trageser
Markus Müschen
Veerle Pertz
John Groffen
Nora Heisterkamp
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2007
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-6-67

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