Review

Leukemia (2005) 19, 687–706. doi:10.1038/sj.leu.2403670 Published online 10 March 2005

Animal models of acute myelogenous leukaemia – development, application and future perspectives

E Mc Cormack1,2, Ø Bruserud1,2 and B T Gjertsen1,2

  1. 1Hematology Section, Institute of Medicine, University of Bergen, Bergen, Norway
  2. 2Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

Correspondence: Dr BT Gjertsen, Institute of Medicine, Hematology Section, Haukeland University Hospital, University of Bergen, N-5021 Bergen, Norway. Fax: +47 5597 5890; E-mail: bjorn.gjertsen@med.uib.no

Received 16 April 2004; Accepted 16 December 2004; Published online 10 March 2005.

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Abstract

From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.

Keywords:

acute myelogenous leukaemia, rat, mouse, xenograft, genetics

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Introduction

Acute myelogenous leukaemia (AML) is characterised by anomalous proliferation and differentiation of malignant myeloid progenitors. The resultant progeny, or blasts, exhibit early differential blocks and proliferate uncontrollably, accumulating in and rapidly replacing host bone marrow, resulting in haematopoietic insufficiency (granulocytopenia, thrombocytopenia, leucopenia or anaemia) and/or leukocytosis.1 The annual incidence of AML is approximately 1.8 per 100 000 increasing progressively with age to a maximum prevalence of 17.2 per 100 000 adults of 65+ years of age.2 However, even with modern advances in therapeutics3, 4 and improvement in the diagnosis of AML subtypes,1, 5, 6, 7, 8 the majority of patients will die from their disease.

Our understanding of leukaemogenic disease pathogenesis has to a large extent been derived from several decades of research on human subjects.4 However, experimental insight into the preliminary events of the leukaemogenic process before they become clinically perceptible is unfeasible in human subjects. Thus, the use of animal models of leukaemia serves the function of making the disease accessible to experimentation impossible in human patients, with the objective of the experimental approach to extend the knowledge of disease pathogenesis and development of new therapeutic regimes.9

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Early murine leukaemic models

Chemically induced models

The initial development and innovation of chemotherapeutic agents of clinical value in the treatment of acute leukaemias were discovered by initial screening against mouse leukaemias and lymphomas.10 In particular, the transplantable leukaemias L121011 and P388,12 chemically induced via 3-methylcholantrene (3-MC) in DBA/2 mice, have been the most successful broad-spectrum screening tools for prioritisation of drugs presented for clinical trial. Leukaemic cell lines have played essential roles in the verification of antileukaemic activity of explicit classes of chemotherapeutics. For example, although used extensively throughout the classes, L1210 has been particularly useful in the screening of antimetabolites11, 13, 14, 15, 16 and anthracyclines,17, 18 P388 is more sensitive towards natural products, topoisomerase II inhibitors19, 20 and amsacrine (AMSA),21 while other lines such as P1534, P815, B82, L5178Y and EARAD 1 have been used for screening vinca alkaloids,22 anilides,23 fluorinated pyrimidines24 and asparaginases,25, 26 respectively. Additionally, through the pioneering work of Skipper and Schabel,27, 28 these models have been used to develop much of what we understand today of biochemical, cytokinetic, pharmacologic and toxicological relationships in the design of optimal therapeutic schedules. Indeed, it was from this work that in 196929 1-beta-D-arabinofuranosylcytosin (cytarabine or Ara-C) was first introduced as a single agent in the initial management of adult AML. Although these initial, high growth fraction, transplantable models contributed a great deal to the selection and development of effective chemotherapeutic agents, they are not truly comparable to the pathogenesis of human AML and were more akin to acute lymphocytic leukaemia (ALL) with cell cycling times of 12 h and resulting fatality in approximately 8 days. However, owing to their extreme sensitivity to clinically active drugs, the L1210 and P388 models provide an effective and inexpensive pre-screen model for the identification of inactive substrates.

Spontaneous models

The use of spontaneous leukaemias which are idiopathic or that arise following viral or chemical exposure mimic the clinical condition more accurately. Skipper and Schabel developed bioassays for the detection of leukaemia30 in AKR mice, which carry an oncogenic RNA virus at birth,31 with median cell cycling times comparable to thymic lymphocytes and appreciable nondividing blasts with deficient proliferative potential.32 Their studies suggested that advanced AKR spontaneous leukaemia, with kinetics similar to AML,32 was more akin to human acute leukaemia at the initiation of therapy or in severe relapse and thus was valuable in predicting agents which induced remission, for example, Ara-C,33 cyclophosphamide,33 vincristine,33 daunorubicin34 and doxorubicin.34

However, spontaneous tumours, although resembling human cancers in kinetics and antigenicity, are usually only measurable late in their course, with inconsistent metastatic patterns and poor response to therapy. Subsequent to exposure, comparatively small percentages of animals develop disease and those that do demonstrate variable natural courses, with disease latencies of at least 3 months, where erroneous staging generally renders these models unsuitable for quantitative appraisal of uniform therapeutic response.35 While the induced models represent a decidedly superior paradigm for drug screening and development, in general, spontaneous tumour models, particularly viral models, have their greatest role in studying the biology of leukaemogenesis.

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Viral models

Naturally occurring myeloid leukaemia is rare in both chickens and mice.36 However, the discovery of the avian myeloblastosis virus (AMV)37 and MC2938, 39, 40 virus, which allowed reproducible disease induction in chickens, lead to the discovery of the v-myb oncogene. Further investigations into these and other avian viruses such as E26,41 CMII,40 OK1040, 42 and MH240 have focussed on their transmutation potential and haematopoietic targets in vitro.43, 44 Undoubtedly, however, the mouse, with short gestation periods, bearing large litters and ease of procreation, conserved its destiny as the principal model in cancer research. Thus, myeloid leukaemias induced by murine leukaemia viruses (MuLV) in the mouse piloted the discovery of critical genes crucial to regulation of growth, lineage determination, development and death in haematopoietic precursor cells.45

Insertional mutagenesis

Replication-competent MuLV induce neoplastic disease in a reproducible manner through a process known as insertional mutagenesis, the subject of exhaustive discussion in several excellent reviews,36, 46, 47, 48, 49, 50, 51, 52, 53 and here briefly. Its success in contributing to our knowledge of the genetic basis of myeloid disease resulted in the development of constructive models of several AML subtypes,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68 which are summarised in Table 1.


Retroviral genomes integrate at essentially random sites within the host genome as part of the viral replication cycle. Pending the site of integration and transcriptional orientation of the provirus regarding the cellular gene, the transcriptional control sequences coded within the viral long terminal repeats (LTR) are capable of instigating, augmenting and/or concluding transcription of host sequences, via several mechanisms, resulting in elevated levels of intact or anomalously mutated mRNAs (Figure 1). Occurrence of this integration in tandem with synergistic enhancer/promoter activation propagates high levels of mutant proteins, which may in turn lead to clonal selection, expansion and ultimately disease.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Insertional mutagenesis. The most frequently encountered mechanism of proviral assimilation, enhancer insertion (a), results in amplified expression of host genes via proviral integration 3' or 5' (in a reverse transcriptional orientation) of the gene. The recurrent incidence of this mechanism is attributable to superior flexibility and tolerability of proviral orientation and distance between provirus and gene, resulting in improved efficacy of the standard promoter, while integration at the 3' untranslated site (b) is thought to increase the stability of transitory mRNA. Retroviral integration upstream (or within the 5' domain) of the host target gene with a homologous transcriptional orientation is consequent of the promoter insertion mechanism (c), which results in elevated LTR-promoted constitutive gene activation and transcription. Finally, proviral integration into the transcriptional coding exons (d, e) may result in inactivation or mutation of the protein sequence with ensuing deviant gene products exhibiting anomalous biological functioning. TI: transcription initiation site; pA: polyadenylation signal; SD: splice donor; SA: splice acceptor; LTR: long-terminal repeat.

Full figure and legend (141K)

MuLV models of AML

MuLV mutagenesis is an extremely useful facet as an AML gene discovery contrivance. Exploitation of viral sequences as molecular tags allow identification and cloning of the integration sites, while analysis of the genomic DNA adjacent to the insertional sites have implicated various classes of oncogenes61, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 in the development of murine AML (Table 2). Of particular importance is the BXH-2 model of AML. This recombinant inbred strain developed by crossing C57BL/6J and C3H/HeJ mice, 95% of which develop AML in the first year of life is causative of an inherent replication-competent B-ecotropic MuLV.65 Consequently, all BXH-2 mice are viremic for their entire lifespan with ensuing AML exhibiting, on average three to four somatically acquired,99 clonal, tumour-specific proviral insertions.45, 84 Analysis of these proviral integration sites by inverse PCR (IPCR) has led to the identification of over 90 disease genes implicated in murine AML, emphasising the utility of this model.


There is substantial homology between the genes mutated and identified by proviral tagging in mouse AML and those implicated in the human disease100, 101, 102, 103, 104, 105, 106, 107, 108 as exemplified in the following cases. Firstly, the AML1(Cbfa2, Runx1, Pebp2alphaB)84 oncogene targeted by chromosomal translocation t(8;21), in approximately 12% of AML cases,109 has been shown to play a vital role in the regulatory expression of many genes involved in haematopoietic cell development. Furthermore, absence of AML1 function deregulates the pathways leading to cellular proliferation and differentiation.110 Secondly, the HOXA980, 111 oncogene, a poor prognosis marker in AML,112 is associated with repetitive chromosomal translocations of t(7;11) resulting in the chimeric transactivator protein NUP98–HOX9, implicated in development of myeloproliferative disease (MPD), which may progress to AML. Co-expression and interaction of NUP98–HOX9 with Meis1 has been shown to accelerate disease progression.113 Finally, patients exhibiting mutations in the Nf145, 87, 114 tumour suppressor gene with Ras mutations had markedly shorter complete remission durations,107 through loss of functional regulation of Ras (p21ras) activation in response to GM-CSF. These examples accentuate the significance of transcriptional dysregulation and emphasise the importance of signalling pathways in human AML. While correlation of the roles of additional gene classes intimated by MuLV mutagenesis (Table 2) to the human condition remains to be realised. The significance of results gained thus far promotes its use in further exposition of unidentified oncogenes and misshapen biochemical pathways, imperative to our understanding of human AML.

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Transplantable models

Subsequent to initial clinical and experimental experiences,1, 115, 116, 117, 118 it became evident that a definitive experimental model for AML was essential for the development of new therapeutic advances. Preliminary described mouse models,119, 120, 121, 122, 123 were inadequate subsequent to poor transplantability, difficulties in separating extramedullary haematopoiesis and leukemoid reactions from true leukaemia,124 with an inability to perform extracorporeal blood experimentation.9 While incidence of spontaneous myelogenous leukaemia in rats is sparsely noted within the literature,120, 125, 126, 127 chemically induced leukaemia met with triumph. Following initial inductions of myelogenous leukaemia employing largely polynuclear aromatic hydrocarbons,128, 129 several transplantable AML rat models9, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 became available (Table 3 and reviewed150, 151). Primarily, the Wistar/Furth,152 L5222 acute rat leukaemia in BDIX142 and the BNML9 rat models, all with predictable growth characteristics,138, 153, 154 analogous biology to human AML,142, 143, 155, 156 ease of transplantability with excellent levels of engraftment9, 138 and similar susceptibility to clinical chemotherapeutic regimes employed in human AML138, 157, 158 emerged as suitable experimental models. However, in comparative colony-forming (CFU-s) studies,143, 159 it was soon realised that the BNML rat model was more characteristic of human AML in its progression and haematological pathology.


The BNML model, first induced by i.v. infusion of dimethylbenz(a)anthracene (DMBA) in 1971, was described as a slow progressing leukaemia with extreme suppression of normal myeloid haematopoiesis.9 Subsequently, various aspects of this model and its derived cell lines (known as IPC-81160, 161, 162 and also as LT-12) in vivo9, 159, 163, 164, 165 and in vitro143, 166, 167 growth characteristics168, 169, 170, 171, 172, 173 and cytogenetics174, 175, 176 have been extensively studied. Analysis of the interaction177 of normal haematopoietic and leukaemic cells in the BNML rat model has proved critical to understanding of mechanisms involved in the kinetics170, 178, 179 and inhibition of normal human haematopoiesis.180, 181 Additionally, endeavours to induce remission by extracorporeal irradiation of the blood (ECIB)182, 183, 184 in this model imparted significant insight into the mobilisation of leukaemic cells between various cell compartments.185, 186 The BNML rat model has also been evaluated in appraising therapeutic index, optimisation of dose schedules and combinations of anthracyclines,187, 188, 189, 190, 191, 192, 193 Ara-C,158, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 AMSA209 and several other therapeutics.210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220

The concern of relapse following autologous bone marrow transplant (ABMT) in human AML was initially addressed in the BNML rat model, examining antileukemic effects as well as toxicity of various conditioning regimes prior to ABMT,221, 222 including total body irradiation (TBI),223 marrow ablative chemoradiotherapy,224, 225, 226, 227, 228, 229, 230, 231, 232 biophysical separation of leukaemic cells from graft marrow233, 234, 235 and in vitro chemotherapy.161, 236, 237, 238, 239 Failure of allogenic bone marrow transplantation due to graft-versus-host disease (GvHD)240, 241, 242, 243, 244, 245, 246 and/or interstitial pneumonitis (IP)247, 248 has also been investigated in this model.247 Undoubtedly, however, the greatest contribution made by the BNML model has been in providing an experimental basis for evolutional clinical studies into the detection and treatment of minimal residual disease (MRD).

MRD detection and treatment in BNML

MRD-derived relapse is the foremost source of fatality in AML patients receiving intensive chemotherapy.249, 250, 251, 252, 253 Detection of MRD and enumeration of leukaemic cells in various organs was elucidated through several different parameters in the BNML rat model.9, 174, 175, 176, 254, 255, 256 These pilot experiments into detection of MRD in the BNML model have lead to significant improvements in clinical MRD detection with flow karyotyping174 and multidimensional flow cytometry.249, 255

Optimisation of therapeutic regimes and examination of growth kinetics257, 258 of the MRD phase of AML subsequent to remission induction,259 have been comprehensively analysed in the BNML rat model for Ara-C,260 cyclophosphamide,227 Dinaline214 and immunotherapy with the Bacillus Calmette-Guérin (BCG)261 vaccination. Furthermore, several drug-resistant BNML-derived cell lines of the more frequently administered chemotherapeutics, for example, Ara-C,262, 263 cyclophosphamide264, 265 and daunorubicin266 (also the experimental chemotherapeutic acetyldinaline267) were developed and now serve as successful in vivo preclinical models for the study of intrinsic or acquired resistance by these drugs. Subsequently, sensitive and resistant BNML rat models have been employed in the preclinical evaluation of several novel treatment modalities. Prominent examples include differentiation induction therapy, developed from preliminary studies with cyclic adenosine monophosphate (cAMP) inducing cholera toxin in the BNML and BNML-cholera toxin-resistant models,161, 268 experimentation with cytokines245, 269, 270, 271, 272 and monoclonal antibodies (mAbs)269 circuitously leading to the clinical studies of agents such as theophylline273 (cAMP induction/stabilisation), Gemtuzumab ozogamicin274 (conjugated mAb) and granulocyte colony-stimulating factor275 (G-CSF-cytokine). These results and the application of the BNML rat model in more recent work pertaining to angiogenesis and microenvironmental modifications by Iversen et al276, 277, 278, 279 rationalise continued interest in this model.

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Xenograft models

Although the transplant model systems, particularly the BNML rat model, have proven invaluable experimental tools, translation of this data to the human condition demands more accurate preclinical models. Expansion of AML in vitro culture systems are generally limited to immortalised cell lines, short-term culture of primary explants and assays on clinical samples.280, 281, 282 These in vitro models fail to engage decisive issues such as cellular/environmental interactions, invasiveness and angiogenesis in AML, thus necessitating development of a relevant xenotransplantation animal model.

Nude models

Initial attempts to xenograft human (hu) AML focussed on subcutaneous transplantation of bone marrow into heavily immunocompromised mice283 and athymic nude (nu) mice.284 Athymic mice are homozygous for the nude (nu) gene (Foxn1nu, previously Hfh11nu or nu/nu),285 and lack functional T and B cells. However, transplantation of normal as well as leukaemic haematopoietic tissues proved difficult to propagate in these models.286, 287 Unfortunately however, even with heavy immunosuppression of nu mice with radiation,286, 287, 288 drugs,289 antibodies287 and in some cases splenectomy (SI),287, 288 xenografting of myeloid leukaemias proved inconsistent and unreliable. Greater success was achieved with human (HL-60,290, 291, 292, 293, 294 KG-1,291, 295 K562,291 MO7E296 and TF-1296, 297) and various allogenic cell lines, including Ba/F3298, 299 and M1-lines,287, 290, 300, 301, 302, 303, 304 which were subsequently employed principally in the further study of AML biology, but also in the development of treatment modalities.292, 298, 301, 305, 306, 307 The major limitation of this initial model was reproducible growth only as localised myelosarcomas, little evidence of bone marrow engraftment,308 with variant kinetics of invasive potential293 and differentiation291 also observed. Efforts to develop further immunodeficient models resulted in the generation of mice which are triply homozygous for the nu, beige (Lystbg, and henceforth bg), reducing the number of natural killer (NK) cells, and X-linked immunodeficiency (Btkxid, and henceforth xid), which decreases the number of lymphokine-activated killer (LAK) cells, loci,309, 310, 311 and mice deficient for the recombination-activating gene-1 (Rag1)312 and Rag2.313 Initial reports describing engraftment of human myeloid tissues using bg/nu/xid mice suggested seeding, proliferation and differentiation of human stem cells.310 Nevertheless, later efforts to engraft human peripheral blood lymphocytes (hu-PBLs) proved difficult,314, 315 while comparative studies in a further immunodeficient model, the scid mouse, resulted in more favourable engraftment.316, 317

SCID models

Severe combined immunodeficient (scid) mice were first described in 1983318 as exhibiting an autosomal recessive mutation of chromosome 16, resulting in disruption of the protein kinase DNA-activated catalytic polypeptide (Prkdc) gene.319, 320, 321, 322, 323 Dysfunctional Prkdc genes effect deactivation of a DNA recombinase enzyme, resulting in inability to express rearranged antigen receptors324, 325 and thus innate deficiency in humoral and cellular immunity, with scid mice lacking functional T and B lymphocytes.326 This model and those following in the remainder of this section have been used extensively to study normal human haematopoiesis, but for the purposes of this review the authors will focus only on human AML xenografts and refer the reader to some excellent reviews for the latter.327, 328, 329, 330, 331, 332, 333 The first successful report of human stem cell engraftment into a scid mouse was reported in 1988316 following transplantation of human foetal tissues with subsequent engraftment of hu-AML into scid recipients in 1991.334 Consequent studies280, 334, 335, 336, 337, 338, 339, 340, 341, 342 resulted in the inchoate identification of the CD34+CD38- scid leukaemia initiating cell (SL-IC)335, 343 whose phenotype is similar to normal HSCs, and the finding that AMLs of differing FAB classifications which engrafted in scid recipients faithfully recapitulated their intrinsic pathological and clinically observed disparities.335, 339 The significance of these results was eclipsed by major practical and limiting considerations. Critically, engraftment levels of hu-cells were low, demonstrating merely 0.5–5% of the marrow population in the engrafted scid recipient,344 resultant of lack of species crossreactivity in cytokines and innate host resistance. While supplementation of these recipients with exogenous human growth factors including interleukin 3 (IL-3),345, 346 IL-6,345 granulocyte-macrophage-colony stimulating factor (GM-CSF),345, 346 a fusion protein of IL-3 and GM-CSF (PIXY321),335, 344 steel factor (SF),346 mast-cell growth factor (hMGF)335 and erythropoietin (EPO)346 resulted in enhanced engraftment and differentiation of human cells in scid recipients, host immunity curtailed the duration of the graft. Incomplete penetrance or 'leakiness' of the scid mutation, although strain dependant, results in high levels of immunoglobulin (Ig), with up to 90% of old mice exhibiting functional lymphocytic rearrangements.347, 348 Additionally, elevated levels of NK cell activity, haemolytic complement and normal granulocyte and macrophage function mediate host resistance,349 abrogating xenograft potential in this model. Several attempts have been made to purge NK cells from scid recipients through the pretreatment with radiation and/or anti-asialo-GM1 antibody,350, 351, 352, 353 which though increasing short-term engraftment shortened survival of the recipient. Nevertheless, further development of this immunodeficient model led to generation of the NOD-scid strain of mice, which allowed comparatively superior engraftment of human haematopoietic stem cells to scid mice.343, 346, 354, 355, 356

Nonobese diabetic mice with severe combined immunodeficiency disease (NOD/SCID) exhibit multiple defects in adaptive and innate immunologic function. These include lack of functional lymphoid cells, exhibiting little or no serum Ig with age.349 They are deficient in C5 and are thus unable to generate haemolytic complement activation,349 demonstrate a paucity of NK cell activity and are poor macrophage secretors of IL-1, indicating functionally less mature macrophage population in comparison to the parental scid strain.349 Additionally, NOD/SCID mice are both insulitis- and diabetes-free throughout life.349 Subsequent transplant of NOD/SCID mice with hu-AML357, 358, 359 resulted in appreciably higher engraftment rates using fewer cells,360, 361, 362 with ensuing xenografts preserving observed morphological, phenotypical, genotypical and biological characteristics of the donors AML cells.360, 363, 364, 365, 366, 367 Additionally cells from patients with poor prognostic markers such as FMS-like tyrosine kinase 3 (Flt-3)363, 368, 369 engrafted more efficiently in NOD/SCID mice than general AML cases.363, 370 The superior engrafting potential of this model has facilitated further characterisation and discrimination of the SL-IC cell surface phenotype from normal HSCs.371 SL-ICs have now been found with in CD34+Thy1-, CD34+CD117 (or c-kit)- and CD34+CD71-HLA-DR- subpopulations of the primitive CD34+CD38- fraction, in contrast to normal HSCs357, 358, 365 (with the notable exception of AML-FAB M3,372, 373), and critically, express IL-3 receptor alpha chain (CD123). The engraftment of human AML cells in the NOD/SCID model has subsequently facilitated development of several new treatment modalities.4, 276, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383

Despite the obvious advantages of the NOD/SCID model over all other immunodeficient models, there are still some inherent obstacles. While various strategies, including hu-cytokine supplementation,364, 370, 384, 385, 386 co-transplantation of growth factor-producing cell lines or 'accessory cells'384, 385 have been evaluated, only 70% of all AML samples exhibit detectible engraftment in NOD/SCIDs.364 Additionally, the development of thymic lymphomas by 8.5 months,387 extreme radiosensitivity387 and discernable NK cell activity387 hinder execution of enduring engraftment.

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Genetically engineered models

Transgenic mice

Nonrandom, somatically acquired chromosomal translocations or inversions are the most common genetic anomalies in acute leukaemia, often effecting irregular activation of transcription factors, resulting in differentiation blocks of specific myeloid lineages.109 Frequently, altered gene expression encoding transcriptional oncoproteins interfere with regulatory cascades critical for proliferation, differentiation and survival of normal blood precursors, which can subsequently be studied in transgenic animal models. While transgenic mice may be created 'classically' through direct pronuclear injection of exogenous DNA into fertilised zygotes388, 389, 390 and succeeding implantation into a pseudopregnant female generating transgenic progeny, the method results in indiscriminate integration into the genome and is reliant upon overexpression of the transgene to generate a phenotype. Further alternatives include injection of genetically modified mouse embryonic stem (ES) cells into a blastocyst391, 392, 393 (embryonic day 4.5) or embryonic retroviral infection.394, 395, 396

Extensive use of 'classic' transgenics have been engaged in the generation of translocations involving chromosome 17 associated with APML, directed to the myeloid compartment by expression of exogenous cDNA under the regulation of human myeloid-specific sequences. Subsequently, using the human cathepsin-G (hCG)397 expression vector to direct expression to the promyelocytic compartment, murine models of PML/RARalpha t(15;17),398 PLZF/RARalpha t(11;17),399, 400 NPM/RARalpha t(5;17),399 NuMA/RARalpha t(11;17)(q13;q21)401 and Cyclin A1402 were generated. Additionally, the human MRP8403 expression cassette, expressed in early myeloid progenitors and mature myeloid cells, and CD11b404 regulatory sequences were used to direct PML/RARalpha cDNA to myeloid-monocytic and more differentiated granulocytic compartments in further transgenic models. While the NPM/RARalpha-hCG399 transgenic model exhibited diverse cytological and pathological characteristics from APML to chronic myelogenous leukaemia (CML), both hCG- and hMRP8-PML/RARalpha and Cyclin A1 models mimicked the human APML phenotype. Both hCG- and hMRP8-PML/RARalpha models exhibited complete, although transient, remission upon retinoic acid administration.398, 403, 405 The hCG-PLZF/RARalpha model demonstrated characteristics similar to that of the hCG-PML/RARalpha model, but displayed a diminished differentiation block. Furthermore, as observed in APML patients with t(11;17), no hCG-PML/RARalpha transgenic mice treated with retinoic acid achieved complete remission.400 Although terminal granulocytic differentiation was observed in hCG-PML/RARalpha it was not in hMRP8-PML/RARalpha, while PML/RARalpha under the influence of the CD11b promoter failed to cause leukaemia. Collective analysis of these results suggests that although the PML/RARalpha and PLZF/RARalpha fusion genes are leukaemic, neither is sufficient to induce APML alone.406, 407, 408

Patients with APML represent a relatively homogenous group in comparison to other AML patients who exhibit extreme heterogeneity with regard to cell morphology, genetic abnormalities and effect of intensive chemotherapy. While many of these patients show normal cytogenetics, only those of the more commonly observed AML-associated genetic abnormalities have been investigated in transgenic mice (overviewed in Table 4), including hMRP8-AML1/ETO,409 Hoxa9410 and Bcl-2 models.411 While hMRP8-AML1/ETO transgenic mice only developed AML upon treatment with the DNA alkylating agent N-ethyl-N-nitrosurea (ENU), the Hoxa9 transgenics did not. The Bcl-2 model developed conditions symptomatic of a CMML disease state which upon crossing with B6.MRL-FasIpr/Ipr (Fas-deficient mice), generating a FasIpr/Ipr hMRP8Bcl-2 transgenic model, developed AML M2412-type disease. Penetrance in this model was reported only at 15%, with not all animals bearing mutation exhibiting AML. Furthermore, a PML/RARalpha-Bcl-2 model derived of breeding between hMRP8-PML/RARalpha403 and hMRP8Bcl-2411 transgenic stocks exhibited marked accumulation of immature myeloid progenitors and leukaemic development, in comparison to singly transgenic hMRP8-PML/RARalpha mice, with all mice capitulating to acute leukaemia by 7 months.413 These results further corroborate the general findings of the APML transgenic models, whereby single mutations were not sufficient to inactuate a replicable AML disease state alone, but only with accrual of further syngenic genetic mutations. Additionally, they can be used to study and identify multi-step leukemic transformation from low-grade to aggressive haematologic malignancies. The hCG-NuMa/RARalpha model is, however, the exception, whose mutation was singularly sufficient for disease development and progression, characterised by complete penetrance and rapid development of leukaemia with a phenotype very similar to human APML.401


Knockin mice

In this approach, the mutated exogenous cDNA is targeted in-frame directly to a predefined locus by homologous recombination in the ES cells. This technique was employed in developing several murine models, namely AML1-ETO t(8;21),414, 415 PLZF-RARalpha t(11;17),406 CBFbeta-MYH11 inv(16) t(16;16),416 CBFbeta-GFP417 and MLL-AF9 t(9;11)418 by targeting these 'knocked in' fusion genes to the normal genetic locus. Ensuing AML1-ETO or CBFbeta-MYH11 knockin fusion genes resulted in embryonic lethality owing to lack of definitive embryonic haematopoiesis. Furthermore, 84% of CBFbeta+/CBFbeta-MYH11 chimeras,419 which do not develop leukaemia in their first year of life, died from AML M4-type disease when administered a single dose of N-ethyl-N-nitrosourea (ENU), inferring that cooperation with further oncogenes is necessary for leukaemogenesis. Additionally, knockin mice heterozygous for MLL-AF9 developed AML with general pathology comparable to FAB M4–5.

Although the results from knockin models are insightful, the approach has several intrinsic disadvantages, most notably the unrestricted expression pattern of the mutated gene. Consequently, several methods were developed for conditional or inducible in vivo gene expression, the details of which are described in several noteworthy reviews.420, 421, 422, 423, 424, 425 A modification of the knockin approach targets mutated genes into loci other than that of the involved gene and whose expression is restricted to the cell type where the aberrant gene is expressed in the human disease. Employing this methodology, a knockin model of PML/RARalpha t(15;17) using the endogenous murine cathepsin G-promoter was generated with 90% incidence of APML in comparison to only 15–20% prevalence observed in the relative hCG-PML/RARalpha model with similar pathology.408 The tetracycline (tet-) inducible424, 426, 427, 428 and Cre/loxP-mediated420, 421, 424, 425, 428 interchromasomal translocation recombination systems have been utilised in generation of inducible models of AML1/ETO t(8;21)429, 430, 431 and MLL/AF9 t(9;11).432 In both the tet-off and Cre-loxP models for AML1/ETO,430, 431 the transcriptional control of AML1/ETO fusion protein was highly expressed in bone marrow; however, as noted in the hMRP8-AML1/ETO model, there was no development of leukaemic phenotype unless expressed in tandem with cooperating mutations.

Knockout mice

The most prevalent genetic experimental approach is to ablate ('knockout') the function of the target gene by replacing it with an altered or nonsense gene. To investigate the normal function of specific genes targeted by translocations in AML, knockout models of AML1,433 CBFbeta434 and PML435 were generated. While these models are not direct AML models, they are commanding instruments in the molecular genetic analysis of normal genes targeted by chromosomal aberrations in AML.

Retroviral transduction and transplantation

Significant efforts have focussed on transfer of AML disease genes into murine haematopoietic cells that subsequently can be transplanted into autologous or syngenic recipients. Such systems circumvent the issue of embryonic lethality observed in some traditional transgenic approaches, allowing targeting of human oncogenes into haematopoietic stem and progenitor cells and subsequently development of chimeric AML models.

Haematopoietic abnormalities, including a significant increase in immature eosinophilic myelocytes, as observed in patients with t(8;21), were replicated in C57BL/6-/Ly-5.1-transplanted mice436 following retroviral transfection of AML/ETO into an enriched HSC population from congenic C57BL/6-GFP+/Ly-5.2 mice. Nevertheless, as with previous transgenic models expressing the AML1-ETO fusion protein,409, 414, 415, 430, 431 no primary or disseminated leukaemia was observed. Subsequently, AML/ETO t(8;21) was transduced to bone marrow derived from mice deficient of the interferon regulatory factor ICSBP,437 implicated as a suppressor of myeloid neoplasia,438, 439, 440 and was found to synergise with ICSBP deficiency to incite myeloblastic conditions evocative of AML. Furthermore, activating mutations in receptor tyrosine kinases, for example, TEL/PDGFbetaR and Flt3 – present in approximately 30% of AML cases, were found to cooperate with AML1/ETO,441 NUP98/HOXA9 t(7;11)442 and PML/RARalpha t(15;17)443 causing AML-M2 type leukaemia, AML and APL, respectively, in transduced mice. Concurrently, cotransduction of murine HSCs with mutated tyrosine kinase BCR/ABL and translocation of NUP98/HOXA9 resulted in AML following transplantation into syngenic mice.442

The technique of retroviral transduction and transplantation was also applied to the genesis of MLL/ELL t(11;19)444 and to AML1/MDS1/EVI1 t(3;21)445 murine models. Induced disease states which recapitulated that of the equivalent human phenotype but with long disease latencies were observed, suggesting that translocated genes, although crucial for AML induction, obligate acquisition of further genetic abnormalities to induce advanced disease. Subsequently, cotransduction and transplantation of doubly BCR/ABL-AML1/MDS1/EVI1,446 Hoxa9-Meis1447 and Hoxa9-E2A/Pbx1448 transfected cells into syngeneic recipients yielded aggressive AML diseases of short latencies, in comparison to singly transducted and transplanted animals.

Genetically engineered models – concluding remarks

While a large number of genetically engineered AML models have been described, it is our opinion that while the major contribution of these studies is to our understanding of leukaemogenesis as a multistep process, the clinical relevance is quite limited. Subsequently, the following conclusions can be drawn:

  • These studies have confirmed that investigated oncogenes and ensuing animal disease often exhibit phenotypic similarities observed in corresponding human disease, suggesting their involvment in the development of hu-AML. This is best documented for the APL models.
  • A major part of the studies with transgenic mice, knockin mice and retroviral transduction/transplantation conclude that leukemogenesis in AML is a multistep process.
  • Only a limited number of genetic abnormalities have been investigated. It cannot be known whether these observations are relevant for larger groups of patients with normal cytogenetics or uncommon cytogenetic abnormalities.
  • It should be emphasised that it is not known whether these genetically manipulated animal models can be used for preclinical evaluation of new therapeutic approaches that target the oncogene/oncoprotein.

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Future perspectives

In the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs, it is essential that current murine AML models, abetted by revolutions of molecular biological and genomic eras, are further developed to exploit more specific, targeted therapeutics. Additionally, the failure of significant numbers of new drugs in late clinical trials necessitates the use of more salient, higher throughput, prognostic preclinical animal models. A significant hindrance to this development has been the limitation in our ability to detect, monitor and quantify the etiology of haematological malignancies in vivo. Thus, critical to the development of these models is the requisition of relevant, continuous, noninvasive and quantitative in vivo AML cellular and molecular imaging modality(s). Imaging of animals in vivo at multiple time points over the course of a disease or treatment regime allows researchers a better appreciation of disease pathology, response to treatment and drug pharmacokinetics. While current imaging strategies increase the predictive accuracy of new drug candidates, they are unsuitable for evaluation MRD, the foremost problem in current AML therapy.

From the early inception of the transplant models through to contemporary xenographic and genetic models, evolution of the murine model system has been critical to our comprehension and treatment of AML. However, with many recent failures of new therapeutic strategies, one must question the current application of these model systems. While current logic leads us to believe that NOD/SCID xenograft and genetic/transgenic mouse models are by far the superior epitomes, one must question the validity of this ideology. While these models have certainly been fundamental to our current understanding of leukemogenesis, they may not be sufficient for the further development necessary in the evolution of more optimal AML models.449, 450, 451, 452, 453

Following the sequencing of the Brown Norwegian rat genome, it should be possible to exploit what we have learned from the mouse and relate it to this more physiologically, pharmacologically, toxicologically and pathologically significant animal. Recent breakthroughs in controlling egg activation454 have in addition paved the way for the development of genetically manipulated rats. Combining the use of such models should offer more pertinent preclinical data, thus reducing current expenditure on drug development and afford greater clinical success.

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Acknowledgements

This study was supported by the Norwegian Cancer Society (Kreftforeningen), Helse Vest HF research grant, and the Norwegian Research Council Functional Genomics Program (FUGE) grant no. 151859. Additionally, we thank Tore-Jacob Raa and Rolf Bjerkvig for enlightening discussions and help.