Abstract
The Ph chromosome has been genetically linked to CML and ALL. Its chimeric fusion gene product, BCR–ABL, can generate leukemia in mice. This review will discuss selected model systems developed to study BCR–ABL induced leukemia and focuses on what we have learned about the human disease from these models. Five main experimental approaches will be discussed including: (i) Reconstitution of mice with bone marrow cells retrovirally transduced with BCR–ABL; (ii) Transgenic mice expressing BCR–ABL; (iii) Knock-in mice with BCR–ABL expression driven from the endogenous bcr locus; (iv) Development of CML-like disease in mice with loss of function mutations in heterologous genes; and (v) ES in vitro hematopoietic differentiation coupled with regulated BCR–ABL expression.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abelson HT, Rabstein LS . 1970 Cancer Res. 30: 2213–2222
Afar DEH, Goga A, McLaughlin J, Witte O, Sawyers CL . 1994 Science 264: 424–426
Afar DEH, Han L, McLaughlin J, Wong S, Dhaka A, Parmar K, Rosenberg N, Witte ON, Colicelli J . 1997 Immunity 6: 773–782
Afar DEH, McLaughlin J, Sherr CJ, Witte ON, Roussel MF . 1995 Proc. Natl. Acad. Sci. USA 92: 9540–9544
Akashi K, Traver D, Miyamoto T, Weissman IL . 2000 Nature 404: 193–197
Amarante-Mendes GP, McGahon AJ, Nishioka WK, Afar DE, Witte ON, Green DR . 1998 Oncogene 16: 1383–1390
Anderson SM, Mladenovic J . 1996 Blood 87: 238–244
Bakiri L, Lallemand D, Bossy-Wetzel E, Yaniv M . 2000 EMBO J. 19: 2056–2068
Bedi A, Barber JP, Bedi GC, el-Deiry WS, Sidransky D, Vala MS, Akhtar AJ, Hilton J, Jones RJ . 1995 Blood 86: 1148–1158
Ben-Neriah Y, Daley GQ, Mes-Masson A-M, Witte ON, Baltimore D . 1986 Science 233: 212–214
Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Regenass U, Lydon NB . 1995 Proc. Natl. Acad. Sci. USA 92: 2558–2562
Cambier N, Zhang Y, Vairo G, Kosmopoulos K, Metcalf D, Nicola NA, Elefanty AG . 1999 Oncogene 18: 343–352
Castellanos A, Pintado B, Weruaga E, Arévalo R, López A, Orfao A, Sánchez-García I . 1997 Blood 90: 2168–2174
Chan LC, Karhi KK, Rayter SI, Heisterkamp N, Eridani S, Powles R, Lawler SD, Groffen J, Foulkes JG, Greaves MF, Wiedemann LM . 1987 Nature 325: 635–637
Chung S-W, Chen H, Wong PMC . 1996 Oncogene 13: 2397–2405
Chung S-W, Wong PMC, Durkin H, Wu YS, Petersen J . 1991 Proc. Natl. Acad. Sci. USA 88: 1585–1589
Clark SS, Chen E, Fizzotti M, Witte ON, Malkovska V . 1993 J. Virol. 67: 6033–6046
Clark SS, McLaughlin J, Crist WM, Champlin R, Witte ON . 1987 Science 235: 85–88
Clarkson B, Strife A . 1993 Leukemia 7: 1683–1721
Clarkson BD, Strife A, Wisniewski D, Lambek C, Carpino N . 1997 Leukemia 11: 1404–1428
Cleveland JL, Dean M, Rosenberg N, Wang JYJ, Rapp UR . 1989 Mol. Cell. Biol. 9: 5685–5695
Colleoni GW, Yamamoto M, Kerbauy J, Serafim RC, Lindsey CJ, Costa FF, Grignolli CR, Saad ST . 1996 Am. J. Hematol. 53: 277–278
Cortez D, Kadlec L, Pendergast AM . 1995 Mol. Cell. Biol. 15: 5531–5541
Daley GQ, Van Etten RA, Baltimore D . 1990 Science 247: 824–830
Deininger MW, Goldman JM, Melo JV . 2000 Blood 96: 3343–3356
Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF . 1994 Blood 83: 3068–3076
Delforge M, Boogaerts MA, McGlave PB, Verfaillie CM . 1999 Blood 93: 284–292
Diekmann L, Beelen DW, Quabeck K, Becher R, Schulte Holthausen H, Butzler R, Schaefer UW, Opalka B . 1994 Acta Haematol. 92: 169–175
Driggers PH, Ennist DL, Gleason SL, Mak WH, Marks MS, Levi BZ, Flanagan JR, Appella E, Ozato K . 1990 Proc. Natl. Acad. Sci. USA 87: 3743–37477
Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . 2001 N. Engl. J. Med. 344: 1084–1086
Eklund EA, Jalava A, Kakar R . 1998 J. Biol. Chem. 273: 13957–13965
Eklund EA, Kakar R . 1999 J. Immunol. 163: 6095–6105
Elefanty AG, Cory S . 1992 Mol. Cell. Biol. 12: 1755–1763
Elefanty AG, Hariharan IK, Cory S . 1990 EMBO J. 9: 1069–1078
Engelman A, Rosenberg N . 1987 Proc. Natl. Acad. Sci. USA 84: 8021–8025
Engelman A, Rosenberg N . 1990 J. Virol. 64: 4242–4251
Era T, Witte ON . 2000 Proc. Natl. Acad. Sci. USA 97: 1737–1742
Fabbiano F, Santoro A, Felice R, Catania P, Cannella S, Majolino I . 1998 Haematologica 83: 856–857
Fainstein E, Marcelle C, Rosner A, Canaani E, Gale RP, Dreazen O, Smith SD, Croce CM . 1987 Nature 330: 386–388
Fialkow PJ, Gartler SM, Yoshida A . 1967 Proc. Natl. Acad. Sci. USA 58: 1468–1471
Fialkow PJ, Jacobson RJ, Papayannopoulou T . 1977 Am. J. Med. 63: 125–130
Ghaffari S, Daley GQ, Lodish HF . 1999 Leukemia 13: 1200–1206
Gishizky ML, Johnson-White J, Witte ON . 1993 Proc. Natl. Acad. Sci. USA 90: 3755–3759
Goga A, McLaughlin J, Afar DEH, Saffran DC, Witte ON . 1995 Cell 82: 981–988
Golub TR, Goga A, Barker GF, Afar DE, McLaughlin J, Bohlander SK, Rowley JD, Witte ON, Gilliland DG . 1996 Mol. Cell. Biol. 16: 4107–4116
Gross AW, Zhang X, Ren R . 1999 Mol. Cell. Biochem. 19: 6918–6928
Gutterman JU . 1994 Proc. Natl. Acad. Sci. USA 91: 1198–1205
Haferlach T, Winkemann M, Ramm-Petersen L, Meeder M, Schoch R, Weber-Matthiesen K, Schlegelberger B, Schoch C, Ludwig WD, Hiddemann W, Loffler H . 1997 Br. J. Haematol. 99: 452–459
Hao SX, Ren R . 2000 Mol. Cell. Biol. 20: 1149–1161
Hariharan IK, Adams JM, Cory S . 1988 Onc. Res. 3: 387–399
Hariharan IK, Harris AW, Crawford M, Abud H, Webb E, Cory S, Adams JM . 1989 Mol. Cell. Biol. 9: 2798–2805
Hawley RG, Lieu FHL, Fong ZC, Hawley TS . 1994 Gene Ther. 1: 136–138
Heisterkamp N, Jenster G, Kioussis D, Pattengale PK, Groffen J . 1991 Transgenic Res. 1: 45–53
Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J . 1990 Nature 344: 251–253
Heisterkamp N, Stam K, Groffen J, de Klein A, Grosveld G . 1985 Nature 315: 758–761
Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse III HC, Ozato K, Horak I . 1996 Cell 87: 307–317
Holyoake T, Jiang X, Eaves C, Eaves A . 1999 Blood 94: 2056–2064
Honda H, Fujii T, Takatoku M, Mano H, Witte ON, Yazaki Y, Hirai H . 1995 Blood 85: 2853–2861
Honda H, Oda H, Suzuki T, Takahashi T, Witte ON, Ozawa K, Ishikawa T, Yazaki Y, Hirai H . 1998 Blood 91: 2067–2075
Huettner CS, Zhang P, Van Etten RA, Tenen DG . 2000 Nat. Genet. 24: 57–60
Hupp TR, Lane DP, Ball KL . 2000 Biochem. J. 352: 1–17
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . 1999 Proc. Natl. Acad. Sci. USA 96: 12804–12809
Kabarowski JHS, Allen PB, Wiedemann L . 1994 EMBO J. 13: 5887–5895
Kabarowski JHS, Witte ON . 2000 Stem Cells 18: 399–408
Kantarjian HM, Talpaz M, Dhingra K, Estey E, Keating MJ, Ku S, Trujillo J, Huh Y, Stass S, Kurzrock R . 1991 Blood 78: 2411–2418
Kasprzyk A, Harrison CJ, Secker-Walker LM . 1999 Leukemia 13: 2000–2006
Kelliher M, Knott A, McLaughlin J, Witte ON, Rosenberg N . 1991 Mol. Cell. Biol. 11: 4710–4716
Kelliher MA, McLaughlin J, Witte ON, Rosenberg N . 1990 Proc. Natl. Acad. Sci. USA 87: 6649–6653
Kipreos ET, Wang JYJ . 1992 Science 256: 382–385
Konopka JB, Watanabe SM, Witte ON . 1984 Cell 37: 1035–1042
Kurzrock R, Shtalrid M, Talpaz M, Kloetzer WS, Gutterman JU . 1987 Blood 70: 1584–1588
Lazaridou A, Chase A, Melo J, Garicochea B, Diamond J, Goldman J . 1994 Leukemia 8: 454–457
Li S, Gillessen S, Tomasson MH, Dranoff G, Gilliland DG, Etten RAV . 2001 Blood 97: 1442–1450
Li S, Ilaria RL, Million RP, Daley GQ, Van Etten RA . 1999 J. Exp. Med. 189: 1399–1412
Li X, Gong J, Feldman E, Seiter K, Traganos F, Darzynkiewicz Z . 1994 Leuk. Lymph. 13: 65–70
Lim Y-M, Wong S, Lau G, Witte ON, Colicelli J . 2000 Proc. Natl. Acad. Sci. USA 97: 12233–12238
Liu J, Campbell M, Guo JQ, Lu D, Xian YM, Andersson BS, Arlinghaus RB . 1993 Oncogene 8: 101–109
Lord KA, Abdollahi A, Hoffman-Liebermann B, Liebermann DA . 1993 Mol. Cell. Biol. 13: 841–851
Lu D, Liu J, Campbell M, Guo JQ, Heisterkamp N, Groffen J, Canaani E, Arlinghaus R . 1993 Blood 82: 1257–1263
Lugo TG, Pendergast A, Muller AJ, Witte ON . 1990 Science 247: 1079–1082
Mano H, Ishikawa F, Nishida J, Hirai H, Takaku F . 1990 Oncogene 5: 1781–1786
Martiat P, Mecucci C, Nizet Y, Stul M, Phillippe M, Cassiman JJ, Michaux JL, Van den Berghe H, Sokal G . 1990 Leukemia 4: 751–754
Maru Y, Afar DE, Witte ON, Shibuya M . 1996a J. Biol. Chem. 271: 15353–15357
Maru Y, Witte ON, Shibuya M . 1996b FEBS Lett. 379: 244–246
McCormack MP, Gonda TJ . 1999 Oncogene 18: 7109–7199
McWhirter JR, Galasso DL, Wang JYJ . 1993 Mol. Cell. Biol. 13: 7587–7595
McWhirter JR, Wang JYJ . 1991 Mol. Cell. Biol. 11: 1553–1565
McWhirter JR, Wang JYJ . 1993 EMBO J. 12: 1533–1546
Melo JV . 1996 Blood 88: 2375–2384
Melo JV, Gordon DE, Tuszynski A, Dhut S, Young BD, Goldman JM . 1993 Blood 81: 2488–2491
Melo JV, Hochhaus A, Yan XH, Goldman JM . 1996 Br. J. Haematol. 92: 684–686
Melo JV, Myint H, Galton DA, Goldman JM . 1994 Leukemia 8: 208–211
Mitani K, Sato Y, Tojo A, Ishikawa F, Kobayashi Y, Miura Y, Miyazono K, Urabe A, Takaku F . 1990 Br. J. Haematol. 76: 221–225
Mitelman F . 1993 Leuk. Lymphoma 11: 11–15
Mollinedo F, Vaquerizo MJ, Naranjo JR . 1991 Biochem. J. 273: 477–479
Muller AJ, Young JC, Pendergast A-M, Pondel M, Landau NR, Littman DR, Witte ON . 1991 Mol. Cell. Biol. 11: 1785–1792
Nakano T, Kodama H, Honjo T . 1994 Science 265: 1098–1101
Nieborowska-Skorska M, Wasik MA, Slupianek A, Salomoni P, Kitamura T, Calabretta B, Skorski T . 1999 J. Exp. Med. 189: 1229–1242
Nowell PC, Hungerford DA . 1960 Science 132: 1497
Osawa M, Hanada K-i, Hamada H, Nakauchi H . 1996 Science 273: 242–245
Pajor L, Vass JA, Kereskai L, Kajtar P, Szomor A, Egyed M, Ivanyi J, Jakso P . 2000 Leukemia 14: 1122–1126
Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R, Meloni G, Saglio G, Salvatore F, Rotoli B . 1996 Blood 88: 2410–2414
Papadopoulos P, Ridge SA, Boucher CA, Stocking C . 1995 Cancer Res. 55: 34–38
Passegue E, Jochum W, Schorpp-Kistner M, Mohle-Steinlein U, Wagner EF . 2001 Cell 104: 21–32
Passegue E, Wagner EF . 2000 EMBO J. 19: 2969–2979
Pear WS, Miller JP, Xu L, Pui JC, Soffer B, Quackenbush RC, Pendergast AM, Bronson R, Aster JC, Scott ML, Baltimore D . 1998 Blood 92: 3780–3792
Pendergast AM, Gishizky ML, Havlik MH, Witte ON . 1993a Mol. Cell. Biol. 13: 1728–1736
Pendergast AM, Quilliam LA, Cripe LD, Bassing CH, Dai Z, Li N, Batzer A, Rabun KM, Der CJ, Schlessinger J, Gishizky ML . 1993b Cell 75: 175–185
Peters DG, Hoover RR, Gerlach MJ, Koh EY, Zhang H, Choe K, Kirschmeier P, Bishop WR, Daley GQ . 2001 Blood 97: 1404–1412
Ponticelli AS, Whitlock CA, Rosenberg N, Witte ON . 1982 Cell 29: 953–960
Prokocimer M, Rotter V . 1994 Blood 84: 2391–2411
Raitano AB, Halpern JR, Hambuch TM, Sawyers CL . 1995 Proc. Natl. Acad. Sci. USA 92: 11746–11750
Raskind WH, Fialkow PJ . 1987 Adv. Cancer Res. 49: 127–167
Reichert A, Heisterkamp N, Daley GQ, Groffen J . 2001 Blood 97: 1399–1403
Rosenberg N, Witte ON . 1988 Adv. Virus Res. 39: 39–81
Roumiantsev S, De Aos IEA, Varticovski L, Ilaria RL, Etten RAV . 2001 Blood 97: 4–13
Rovira A, Urbano-Ispizua A, Cervantes F, Rozman M, Vives-Corrons JL, Montserrat E, Rozman C . 1995 Ann. Hem. 70: 129–133
Rowley JD . 1973 Nature 243: 290–293
Saglio G, Guerrasio A, Rosso C, Zaccaria A, Tassinari A, Serra A, Rege-Cambrin G, Mazza U, Gavosto F . 1990 Blood 76: 1819–1824
Salloukh HF, Vowles I, Heisterkamp N, Groffen J, Laneuville P . 2000 Oncogene 19: 4362–4374
Sattler M, Salgia R . 1997 Cytokine Growth Factor Rev. 8: 63–79
Sawyers CL, McLaughlin J, Witte ON . 1995 J. Exp. Med. 181: 307–313
Schorpp-Kistner M, Wang ZQ, Angel P, Wagner EF . 1999 EMBO J. 18: 934–948
Scott ML, Van Etten RA, Daley GQ, Baltimore D . 1991 Proc. Natl. Acad. Sci. USA 88: 6506–6510
Secker-Walker LM, Cooke HM, Browett PJ, Shippey CA, Norton JD, Coustan-Smith E, Hoffbrand AV . 1988 Blood 72: 784–791
Sexl V, Piekorz R, Moriggl R, Rohrer J, Brown MP, Bunting KD, Rothammer K, Roussel MF, Ihle JN . 2000 Blood 96: 2277–2283
Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ . 1995 J. Biol. Chem. 270: 13063–13069
Shtivelman E, Lifshitz B, Gale RP, Roe BA, Canaani E . 1985 Nature 315: 550–554
Skorski T, Kanakaraj P, Ku D-H, Nieborowska-Skorska M, Canaani E, Zon G, Perussia B, Calabretta B . 1994 J. Exp. Med. 179: 1855–1865
Skorski T, Nieborowska-Skorska M, Wlodarski P, Perrotti D, Martinez R, Wasik MA, Calabretta B . 1996 Proc. Natl. Acad. Sci. USA 93: 13137–13142
Skorski T, Nieborowska-Skorska M, Wlodarski P, Wasik M, Trotta R, Kanakaraj P, Salomoni P, Antonyak M, Martinez R, Majewski M, Wong A, Perussia B, Calabretta B . 1998 Blood 91: 406–418
Soussi T . 2000 Ann. NY Acad. Sci. 910: 121–139
Takahashi N, Miura I, Saitoh K, Miura AB . 1998 Blood 92: 4758–4763
Tauchi T, Okabe S, Miyazawa K, Ohyashiki K . 1998 Int. J. Oncol. 12: 1269–1276
Thome KC, Radfar A, Rosenberg N . 1997 J. Virol. 71: 8149–8156
Tiribelli M, Tonso A, Ferrro D, Parzilae A, Cambrin GR, Scaravaglio P, Cilloni D, Gottardi E, Saglio G . 2000 Blood 95: 4019–4020
Unnikrishnan I, Radfar A, Jenab-Wolcott J, Rosenberg N . 1999 Mol. Cell. Biol. 19: 4825–4831
Van Etten RA, Jackson PK, Baltimore D, Sanders MC, Matsudaira PT, Janmey PA . 1994 J. Cell. Biol. 124: 325–340
Voncken JW, Griffiths S, Greaves MF, Pattengale PK, Heisterkamp N, Groffen J . 1992a Cancer Res. 52: 4534–4539
Voncken JW, Kaartinen V, Groffen J, Heisterkamp N . 1998 Oncogene 16: 2029–2032
Voncken JW, Karrtinen V, Pattengale PK, Germeraad WTV, Groffen J, Heisterkamp N . 1995a Blood 86: 4603–4611
Voncken JW, Morris C, Pattengale P, Dennert G, Kikly C, Groffen J, Heisterkamp N . 1992b Blood 79: 1029–1036
Voncken JW, Van Schaick H, Kaartinen V, Deemer K, Coates T, Landing B, Pattengale P, Dorseuil O, Bokoch GM, Groffen J, Heisterkamp N . 1995b Cell 80: 719–728
Walker LC, Ganesan TS, Dhut S, Gibbsons B, Lister TA, Rothbard J, Young BD . 1987 Nature 329: 851–853
Wilson G, Frost L, Goodeve A, Vandenberghe E, Peake I, Reilly J . 1997 Blood 88: 2410–2414
Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB . 1996 Cancer Res. 56: 3426–3430
Witte ON, Goff S, Rosenberg N, Baltimore D . 1980 Proc. Natl. Acad. Sci. USA 8: 4993–4997
Witte ON, Ponticelli A, Gifford A, Baltimore D, Rosenberg N, Elder J . 1981 J. Virol. 39: 870–878
Yoffe G, Chinault AC, Talpaz M, Blick MB, Kantarjian HM, Taylor K, Spitzer G . 1987 Exp. Hematol. 15: 725–728
Zhang X, Ren R . 1998 Blood 92: 3829–3840
Zhang X, Subrahmanyam R, Wong R, Gross AW, Ren R . 2001a Mol. Cell. Biol. 21: 840–853
Zhang X, Wong R, Hao SX, Pear WS, Ren R . 2001b Blood 97: 277–287
Zhao RC, Jiang Y, Verfaillie CM . 2001 Blood 97: 2406–2412
Zou X, Cong F, Coutts M, Cattoretti G, Goff SP, Calame K . 2000 Mol. Cell. Biol. 20: 628–633
Acknowledgements
We thank Dr Janusz HS Kabarowski and Lu Quang Le for helpful discussions and critical reading of this manuscript and JC White for the preparation of this manuscript. Work from this laboratory described in the manuscript was supported by funds from the National Cancer Institute and the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wong, S., Witte, O. Modeling Philadelphia chromosome positive leukemias. Oncogene 20, 5644–5659 (2001). https://doi.org/10.1038/sj.onc.1204638
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1204638
Keywords
This article is cited by
-
Differential signaling networks of Bcr–Abl p210 and p190 kinases in leukemia cells defined by functional proteomics
Leukemia (2017)
-
CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia
Journal of Cell Communication and Signaling (2012)
-
Array-based genomic resequencing of human leukemia
Oncogene (2010)
-
CCN3: a key growth regulator in Chronic Myeloid Leukaemia
Journal of Cell Communication and Signaling (2009)
-
IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1
Oncogene (2006)