Abstract
The MLL (Mixed Lineage Leukemia) gene is a common target for chromosomal translocations associated with human acute leukemias. These translocations result in a gain of MLL function by generating novel chimeric proteins containing the amino-terminus of MLL fused in-frame with one of 30 distinct partner proteins. Structure/function studies using an in vitro myeloid progenitor immortalization assay have revealed that at least four nuclear partner proteins contribute transcriptional effector properties to MLL to produce a range of chimeric transcription factors with leukemogenic potential. Mouse models suggest that expression of an MLL fusion protein is necessary but not sufficient for leukemogenesis. Interestingly, whilst all MLL fusion proteins tested so far phenocopy each other with respect to in vitro immortalization, the latency period required for the onset of acute leukemia in vivo is variable and partner protein dependent. We discuss potential mechanisms that may account for the ability of distinct MLL fusion proteins to promote short or long latency leukemogenesis.
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
Ayton, Cleary . 2001 Transcription Factors: Normal and Malignant Development of Blood Cells Ravid K and Licht J (eds) Wiley-Liss: New York pp. 447–463
Bahri SM, Chia W, Yang X . 2001 Mech. Dev. 100: 291–301
Bain G, Maandag EC, Izon DJ, Amsen D, Kruisbeek AM, Weintraub BC, Krop I, Schlissel MS, Feeney AJ, van Roon, M . 1994 Cell 79: 885–892
Bannister AJ, Kouzarides T . 1996 Nature 384: 641–643
Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, Loncarevic IF, Bohle RM, Harbott J, Repp R, Jaeger U, Viehmann S, Henn T, Korth P, Scharr D, Lampert F . 2000 Proc. Natl. Acad. Sci. USA 97: 9168–9173
Borrow J, Stanton Jr VP, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE . 1996 Nat. Genet. 14: 33–41
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME . 1999 Cell 96: 857–868
Cairns BR, Henry NL, Kornberg RD . 1996 Mol. Cell. Biol. 16: 3308–3316
Caligiuri MA, Strout MP, Schichman SA, Mrozek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen-Bjergaard J, Croce CM, Bloomfield CD . 1996 Cancer Res. 56: 1418–1425
Caslini C, Shilatifard A, Yang L, Hess JL . 2000 Proc. Natl. Acad. Sci. USA 97: 2797–2802
Castilla LH, Wijmenga C, Wang Q, Stacy T, Speck NA, Eckhaus M, Marin-Padilla M, Collins FS, Wynshaw-Boris A, Liu PP . 1996 Cell 87: 687–696
Chaplin T, Ayton P, Bernard OA, Saha V, Della Valle V, Hillion J, Gregorini A, Lillington D, Berger R, Young BD . 1995a Blood 85: 1435–1441
Chaplin T, Bernard O, Beverloo HB, Saha V, Hagemeijer A, Berger R, Young BD . 1995b Blood 86: 2073–2076
Cleary ML . 1991 Cell 66: 619–622
Corral J, Lavenir I, Impey H, Warren AJ, Forster A, Larson TA, Bell S, McKenzie AN, King G, Rabbitts TH . 1996 Cell 85: 853–861
Croce CM . 1999 Cancer Res. 59: 1778s–1783s
Cross SH, Meehan RR, Nan X, Bird A . 1997 Nat. Genet. 16: 256–259
Dhalluin C, Carlson JE, Zeng L, He C, Aggarwal AK, Zhou MM . 1999 Nature 399: 491–496
DiMartino JF, Miller T, Ayton PM, Landewe T, Hess JL, Cleary ML, Shilatifard A . 2000 Blood 96: 3887–3893
Dobson CL, Warren AJ, Pannell R, Forster A, Lavenir I, Corral J, Smith AJ, Rabbitts TH . 1999 EMBO J. 18: 3564–3574
Dobson CL, Warren AJ, Pannell R, Forster A, Rabbitts TH . 2000 EMBO J. 19: 843–851
Domer PH, Fakharzadeh SS, Chen CS, Jockel J, Johansen L, Silverman GA, Kersey JH, Korsmeyer SJ . 1993 Proc. Natl. Acad. Sci. USA 90: 7884–7888
Dreyling MH, Martinez-Climent JA, Zheng M, Mao J, Rowley JD, Bohlander SK . 1996 Proc. Natl. Acad. Sci. USA 93: 4804–4809
Dreyling MH, Schrader K, Fonatsch C, Schlegelberger B, Haase D, Schoch C, Ludwig W, Loffler H, Buchner T, Wormann B, Hiddemann W, Bohlander SK . 1998 Blood 91: 4662–4667
Felix CA, Lange BJ . 1999 Oncologist 4: 225–240
Galoian K, Milne T, Brock H, Shilatifard A, Slany R, Hess J . 2000 Blood 96: 457a
Gecz J, Gedeon AK, Sutherland GR, Mulley JC . 1996 Nat. Genet. 13: 105–108
Gu Y, Shen Y, Gibbs RA, Nelson DL . 1996 Nat. Genet. 13: 109–113
Hayette S, Tigaud I, Vanier A, Martel S, Corbo L, Charrin C, Beillard E, Deleage G, Magaud JP, Rimokh R . 2000 Oncogene 19: 4446–4450
He L, Bhaumik M, Tribioli C, Rego EM, Ivins S, Zelent A, Pandolfi PP . 2000 Mol. Cell 6: 1131–1141
Hendrich B, Bird A . 1998 Mol. Cell. Biol. 18: 6538–6547
Hess JL, Yu BD, Li B, Hanson R, Korsmeyer SJ . 1997 Blood 90: 1799–1806
Huth JR, Bewley CA, Nissen MS, Evans JN, Reeves R, Gronenborn AM, Clore GM . 1997 Nat. Struct. Biol. 4: 657–665
Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y . 1997 Blood 90: 4699–4704
Isnard P, Core N, Naquet P, Djabali M . 2000 Blood 96: 705–710
Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J, Takahashi T, Ueda R, Seto M . 1996 Oncogene 13: 1945–1953
Johansson B, Moorman AV, Haas OA, Watmore AE, Cheung KL, Swanton S, Secker-Walker LM . 1998 Leukemia 12: 779–787
Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM . 1999 Nature 398: 630–634
Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, Theil KS, Krahe R, Ruutu T, Knuutila S, Bloomfield CD, Caligiuri MA . 2000 Proc. Natl. Acad. Sci. USA 97: 2145–2150
Kuriyama M, Harada N, Kuroda S, Yamamoto T, Nakafuku M, Iwamatsu A, Yamamoto D, Prasad R, Croce C, Canaani E, Kaibuchi K . 1996 J. Biol. Chem. 271: 607–610
Kuwada N, Kimura F, Matsumura T, Yamashita T, Nakamura Y, Wakimoto N, Ikeda T, Sato K, Motoyoshi K . 2001 Cancer Res. 61: 2665–2669
Lavau C, Szilvassy SJ, Slany R, Cleary ML . 1997 EMBO J. 16: 4226–4237
Lavau C, Du C, Thirman M, Zeleznik-Le N . 2000a EMBO J. 19: 4655–4664
Lavau C, Luo RT, Du C, Thirman MJ . 2000b Proc. Natl. Acad. Sci. USA 97: 10984–10989
Lavau C, Luo RT, Simeone F, Polak PE, Du C, Kawamata S, Thirman MJ . 2000c Blood 96: 573a
Li Q, Frestedt JL, Kersey JH . 1998 Blood 92: 3841–3847
Lochner K, Siegler G, Fuhrer M, Greil J, Beck JD, Fey GH, Marschalek R . 1996 Cancer Res. 56: 2171–2177
Ma C, Staudt LM . 1996 Blood 87: 734–745
Mahgoub N, Parker RI, Hosler MR, Close P, Winick NJ, Masterson M, Shannon KM, Felix CA . 1998 Genes Chromo. Cancer 21: 270–275
Martinez-Balbas MA, Bannister AJ, Martin K, Haus-Seuffert P, Meisterernst M, Kouzarides T . 1998 EMBO J. 17: 2886–2893
Matsuo T, Takahashi K, Kondo S, Kaibuchi K, Yamamoto D . 1997 Development 124: 2671–2680
Medema RH, Kops GJ, Bos JL, Burgering BM . 2000 Nature 404: 782–787
Megonigal MD, Cheung NK, Rappaport EF, Nowell PC, Wilson RB, Jones DH, Addya K, Leonard DG, Kushner BH, Williams TM, Lange BJ, Felix CA . 2000 Proc. Natl. Acad. Sci. USA 97: 2814–2819
Mitelman F, Johansson B, Mertens F . 1994 Catalogue of Chromosome Abberations in Cancer 5th Edn Wiley-Liss: New York
Miller T, Williams K, Johnstone RW, Shilatifard A . 2000 J. Biol. Chem. 275: 32052–32056
Miyamoto H, Nihonmatsu I, Kondo S, Ueda R, Togashi S, Hirata K, Ikegami Y, Yamamoto D . 1995 Genes Dev. 9: 612–625
Morrissey J, Tkachuk DC, Milatovich A, Francke U, Link M, Cleary ML . 1993 Blood 81: 1124–1131
Morrissey JJ, Raney S, Cleary ML . 1997 Leuk. Res. 21: 911–917
Mountford P, Zevnik B, Duwel A, Nichols J, Li M, Dani C, Robertson M, Chambers I, Smith A . 1994 Proc. Natl. Acad. Sci. USA 91: 4303–4307
Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N, Gale RP, Lange B, Crist WM, Nowell PC, Croce CM, Canaani, E . 1993 Proc. Natl. Acad. Sci. USA 90: 4631–4635
Nilson I, Reichel M, Ennas MG, Greim R, Knorr C, Siegler G, Greil J, Fey GH, Marschalek R . 1997 Br. J. Haematol. 98: 157–169
Nissen MS, Langan TA, Reeves R . 1991 J. Biol. Chem. 266: 19945–19952
Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G . 1997 Nature 389: 994–999
Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR . 1996 Cell 84: 321–330
Paradis S, Ruvkun G . 1998 Genes Dev. 12: 2488–2498
Pegram LD, Megonigal MD, Lange BJ, Nowell PC, Rowley JD, Rappaport EF, Felix CA . 2000 Blood 96: 4360–4362
Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ, Breuning MH . 1995 Nature 376: 348–351
Prasad R, Yano T, Sorio C, Nakamura T, Rallapalli R, Gu Y, Leshkowitz D, Croce CM, Canaani E . 1995 Proc. Natl. Acad. Sci. USA 92: 12160–12164
Rabbitts TH . 1994 Nature 372: 143–149
Reeves R, Nissen MS . 1990 J. Biol. Chem. 265: 8573–8582
Reeves R, Langan TA, Nissen MS . 1991 Proc. Natl. Acad. Sci. USA 88: 1671–1675
Rowley JD . 1992 Genes Chrom. Cancer 5: 264–266
Rozenblatt-Rosen O, Rozovskaia T, Burakov D, Sedkov Y, Tillib S, Blechman J, Nakamura T, Croce CM, Mazo A, Canaani E . 1998 Proc. Natl. Acad. Sci. USA 95: 4152–4157
Rubnitz JE, Morrissey J, Savage PA, Cleary ML . 1994 Blood 84: 1747–1752
Sano K, Hayakawa A, Piao JH, Kosaka Y, Nakamura H . 2000 Blood 95: 1066–1068
Schichman SA, Caligiuri MA, Gu Y, Strout MP, Canaani E, Bloomfield CD, Croce CM . 1994 Proc. Natl. Acad. Sci. USA 91: 6236–6239
Secker-Walker LM . 1998 Leukemia 12: 776–778
Shi Y, Alin K, Goff SP . 1995 Genes Dev. 9: 2583–2597
Shilatifard A, Lane WS, Jackson KW, Conaway RC, Conaway JW . 1996 Science 271: 1873–1876
Shilatifard A, Duan DR, Haque D, Florence C, Schubach WH, Conaway JW, Conaway RC . 1997a Proc. Natl. Acad. Sci. USA 94: 3639–3643
Shilatifard A, Haque D, Conaway RC, Conaway JW . 1997b J. Biol. Chem. 272: 22355–22363
Slany RK, Lavau C, Cleary ML . 1998 Mol. Cell. Biol. 18: 122–129
Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD, Zeleznik-Le NJ . 1997 Proc. Natl. Acad. Sci. USA 94: 8732–8737
Strout MP, Mrozek K, Heinonen K, Sait SN, Shows TB, Aplan PD . 1996 Genes Chrom. Cancer 16: 204–210
Su M, Wisotzkey R, Newfeld S . 2001 Genetics 157: 717–725
Syntichaki P, Topalidou I, Thireos G . 2000 Nature 404: 414–417
Taki T, Sako M, Tsuchida M, Hayashi Y . 1997 Blood 89: 3945–3950
Taki T, Shibuya N, Taniwaki M, Hanada R, Morishita K, Bessho F, Yanagisawa M, Hayashi Y . 1998 Blood 92: 1125–1130
Taki T, Kano H, Taniwaki M, Sako M, Yanagisawa M, Hayashi Y . 1999 Proc. Natl. Acad. Sci. USA 96: 14535–14540
Tang AH, Neufeld TP, Rubin GM, Muller HA . 2001 Development 128: 801–813
Thirman MJ, Levitan DA, Kobayashi H, Simon MC, Rowley JD . 1994 Proc. Natl. Acad. Sci. USA 91: 12110–12114
Tkachuk DC, Kohler S, Cleary ML . 1992 Cell 71: 691–700
Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH . 1994 Nature 371: 221–226
Versteege I, Sevenet N, Lange J, Rousseau-Merck MF, Ambros P, Handgretinger R, Aurias A, Delattre O . 1998 Nature 394: 203–206
von Bergh A, Beverloo B, Slater R, Groot A, Rombout P, Kluin P, Schuuring E . 2000 Blood 96: 693a
Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA . 1996 Proc. Natl. Acad. Sci. USA 93: 3444–3449
Wittwer F, van der Straten A, Keleman K, Dickson BJ, Hafen E . 2001 Development 128: 791–800
Yagi H, Deguchi K, Aono A, Tani Y, Kishimoto T, Komori T . 1998 Blood 92: 108–117
Yano T, Nakamura T, Blechman J, Sorio C, Dang CV, Geiger B, Canaani E . 1997 Proc. Natl. Acad. Sci. USA 94: 7286–7291
Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R . 1998 Cell 93: 361–372
Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M, Marin-Padilla M, Tenen DG, Speck NA, Zhang DE . 1997 Natl. Genet. 15: 303–306
Yu BD, Hess JL, Horning SE, Brown GA, Korsmeyer SJ . 1995 Nature 378: 505–508
Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ . 1998 Proc. Natl. Acad. Sci. USA 95: 10632–10636
Zeleznik-Le NJ, Harden AM, Rowley JD . 1994 Proc. Natl. Acad. Sci. USA 91: 10610–10614
Acknowledgements
We thank our colleagues in the Cleary Lab for many helpful discussions and sharing of unpublished results. Our studies are supported in part by funds from the National Cancer Institute.
Author information
Authors and Affiliations
Rights and permissions
This article is cited by
-
Acute lymphoid leukemia etiopathogenesis
Molecular Biology Reports (2021)
-
The impact of fusion genes on cancer stem cells and drug resistance
Molecular and Cellular Biochemistry (2021)
-
Therapeutic strategies against hDOT1L as a potential drug target in MLL-rearranged leukemias
Clinical Epigenetics (2020)
-
Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop in blood malignancies
Cell Death & Disease (2020)
-
SET domain containing protein 5 (SETD5) enhances tumor cell invasion and is associated with a poor prognosis in non-small cell lung cancer patients
BMC Cancer (2019)