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Frontiers of Medicine

Front Med    2012, Vol. 6 Issue (3) : 248-262     DOI: 10.1007/s11684-012-0206-6
REVIEW |
AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches
Megan A. Hatlen1,2, Lan Wang1, Stephen D. Nimer1,2()
1. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; 2. Weill Cornell Medical College, New York, NY 10065, USA
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Abstract

The AML1-ETO fusion transcription factor is generated by the t(8;21) translocation, which is present in approximately 4%–12% of adult and 12%–30% of pediatric acute myeloid leukemia (AML) patients. Both human and mouse models of AML have demonstrated that AML1-ETO is insufficient for leukemogenesis in the absence of secondary events. In this review, we discuss the pathogenetic insights that have been gained from identifying the various events that can cooperate with AML1-ETO to induce AML in vivo. We also discuss potential therapeutic strategies for t(8;21) positive AML that involve targeting the fusion protein itself, the proteins that bind to it, or the genes that it regulates. Recently published studies suggest that a targeted therapy for t(8;21) positive AML is feasible and may be coming sometime soon.

Keywords AML1-ETO      mouse model      leukemia      t(8;21)      pathway hits      mutation      hematopoiesis      Kasumi-1; CD34+     
Corresponding Authors: Nimer Stephen D.,Email:snimer@med.miami.edu   
Issue Date: 05 September 2012
 Cite this article:   
Megan A. Hatlen,Lan Wang,Stephen D. Nimer. AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches[J]. Front Med, 2012, 6(3): 248-262.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-012-0206-6
http://journal.hep.com.cn/fmd/EN/Y2012/V6/I3/248
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Megan A. Hatlen
Lan Wang
Stephen D. Nimer
ModelPhenotypeReference
Transgenic models
AML1-ETO knocked-in to the Cbfα2 locus- Mice died during embryogenesis, 12.5-13.5 days post coitum- Mice showed hemorrhaging in the central nervous system- Fetal liver hematopoiesis was blocked [24]
AML1-ETO knocked-in to the Cbfα2 locus- Mice died during embryogenesis, 12.5-14.5 days post coitum- Mice showed hemorrhaging in the central nervous system- Fetal liver hematopoiesis was blocked [25]
Mice expressing AML1-ETO cDNA under a tetracycline-responsive promoter were bred to mice containing the murine mammary tumor virus-tet controlled transcriptional activator (MMTV-tTA) construct- Mice showed normal hematopoiesis- Bone marrow cells showed enhanced serial replating ability [12]
Mice in which a chromosomal translocation between AML1 and ETO genes could be generated through Cre/loxP-mediated recombination were crossed to Nestin-Cre mice- The translocation was not detectable by PCR in DNA isolated from bone marrow, muscle, and lung. Trace amounts of the translocation were found in DNA isolated from testes, spleen, and liver- No malignancies were detected in mice aged 5 months or younger [11]
Mice expressing AML1-ETO cDNA under the human MRP8 promoter- Mice showed normal hematopoiesis- Treatment of newborn hMRP8-AML1-ETO transgenic mice with N-ethyl-N-nitrosourea resulted in 55% developing AML [14]
Mice with a conditional AML1-ETO knock-in allele (under the endogenous AML1 promoter) were crossed to Mx1-Cre mice.- Mice showed normal hematopoiesis- Bone marrow cells showed enhanced serial replating ability- Treatment with N-ethyl-N-nitrosourea resulted in 31% developing granulocytic sarcoma/AML [13]
Mice contained an AML1-ETO-IRES-eGFP construct under the Ly6A locus- Mice developed a spontaneous myeloproliferative disorder with a penetrance of 52% at 1 year and 82% at 14 months. [15]
Transplantation models
Mouse c-Kit+Sca-1+Lin- bone marrow cells were transduced with the MSCV-AML1-ETO-IRES-eGFP cDNA construct and transplanted into lethally irradiated congenic recipients- Mice showed an increased number of myeloid progenitors and c-Kit+Sca-1+Lin- cells in the bone marrow compartment- No hematopoietic malignancies were detected [32]
Mouse whole bone marrow or whole E14.5 fetal liver cells were transduced with the truncated AML1-ETO cDNA (Mig-A/Etr) construct and transplanted into lethally irradiated recipients. MF-1, BALB c, or C57 mice were used- Mice developed acute myeloid leukemia- MF-1 mice transplanted with transduced MF-1 E14.5 fetal liver cells had a median survival time of 20 weeks post-transplantation- MF-1 eGFP+ splenocytes stained as Lin-, Sca-1-, c-Kit+, FcyRII/IIImed, and CD34- [57]
MF-1 mouse whole E14.5 fetal liver cells were transduced with the AML1-ETO9a cDNA (Migr1-AE9a) construct and transplanted into lethally irradiated MF-1 recipients- The majority of the mice developed acute myeloid leukemia 16 weeks post-transplantation- eGFP+ cells stained as Lin-, Sca-1-, c-Kit+, FcyRII/IIImed, and CD34- [59]
C57BL/6 mouse whole E14.5 fetal liver cells were transduced with the AML1-ETO9a cDNA (Migr1-AE9a) construct and transplanted into lethally irradiated C57BL/6 recipients- Mice developed acute myeloid leukemia and had a median survival time of 25 weeks post-transplantation- eGFP+ cells stained as Lin-, Sca-1-, c-Kit + , FcyRII/IIImed, and CD34- [59]
Whole E14.5 fetal liver cells from MRP8-AE transgenic mice were transduced with the AML1-ETO9a cDNA (Migr1-AE9a) construct and transplanted into lethally irradiated C57BL/6 recipients- The majority of the mice developed acute myeloid leukemia 5 weeks post-transplantation- The eGFP+ Lin-Sca-1-c-Kit+, as well as the eGFP+ Lin-Sca-1+ c-Kit+ cells, were FcyRII/IIIlo–hi and CD34+ [59]
Human CD34+ hematopoietic cells were transduced with the MigR1-AML1-ETO cDNA construct and transplanted into NOD/SCID mice- AML1-ETO expressing CD34+ cells had an enhanced self-renewal and proliferative ability- Engraftment in NOD/SCID mice was limited and did not result in leukemogenesis [111,112]
Human CD34+ hematopoietic cells were transduced with FMEV retrovirus containing the AML1-ETO cDNA construct and transplanted into NOD/SCID mice- AML1-ETO expressing CD34+ cells had an enhanced self-renewal ability- Engraftment in NOD/SCID mice was achieved, but did not result in leukemogenesis [113]
Tab.1  Mouse models of AML1-ETO expression
Fig.1  Mouse models have demonstrated that AML1-ETO, the fusion protein generated by the t(8;21) translocation in AML, is insufficient for leukemogenesis. This diagram depicts the genes whose misexpression or mutation have been detected in t(8;21) positive AML patients and the overall pathway effects that they might produce [-]. These “hits” in the pathways of differentiation, apoptosis, self-renewal, growth, and proliferation, as well as other pathways, may ultimately collaborate with AML1-ETO to initiate and/or maintain AML.
InhibitorTargetTarget cellPhenotypeReference
ABT-737Bcl-2 family membersAML1-ETO and N-RasG12D coexpressing CD34 + cells- Decreased cell growth [85]
ALLN and calpain inhibitor IIICalpainsKasumi-1 cells- Decreased viability- Decreased colony formation- Degraded endogenous AML1-ETO protein [88]
TSAClass I and II HDACsKasumi-1 cells- Reduced the half-life of AML1-ETO protein- Induced apoptosis [100]
DEPClass I HDACsKasumi-1 cells t(8;21) AML patient bone marrow cells- Reduced the half-life of AML1-ETO protein- Induced apoptosis- Released AML1-ETO from HSP90- Upregulated ANXA1 [102]
17-AAGHSP-90Kasumi-1 cells t(8;21) AML patient bone marrow cells- Reduced the half-life of AML1-ETO protein [102]
SAHAClass I and II HDACsKasumi-1 cells- Induced apoptosis- Upregulated ANXA1 [117]
Methyl-prednisoloneCorticosteroid targetsKasumi-1 cells- Reduced colony formation ability- Induced myeloid differentiation- Induced apoptosis- Synergized with ARA-C and daunorubicin [89]
MethotrexateDihydrofolate reductaseKasumi-1 cellsNOD/SCID transplanted with SKNO-1 cells- Reduced colony formation ability- Induced myeloid differentiation- Induced apoptosis- Reduced tumor burden [89]
NS-398COX-2AML1-ETO transgenic Zebrafish embryosK562 cells transduced with AML1-ETO- Restored GATA1 expression- Removed the block in erythroid differentiation [91]
Eri-BUnknownAML1-ETO positive cell linest(8;21) AML patient bone marrow cellsC57 mice transplanted with cells expressing truncated AML1-ETONude mice inoculated with Kasumi-1- Induced apoptosis- Increased median survival- Reduced tumor volume of nude mice [93]
TriptolideUnknownAML1-ETO positive cell linest(8;21) AML patient bone marrow cells- Inhibited growth and proliferation [94]
BortezomibProteosome inhibitorAML1-ETO positive cell linest(8;21) AML patient bone marrow cellsC57 mice transplanted with cells expressing truncated AML1-ETO- Induced apoptosis- Inhibited growth and proliferation- Increased median survival [96]
Lys-CoA-Tatand C646p300AML1-ETO positive cell linest(8;21) AML patient bone marrow cellsLeukemic AML1-ETO9a positive mouse cells- Inhibited growth and proliferation- Increased median survival of secondary transplant recipients [107]
Tab.2  Chemical inhibitors with therapeutic potential for t(8;21) positive AML
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