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Stem Cells, Vol. 18, No. 3, 157-165, May 2000
© 2000 AlphaMed Press

Concise Reviews

New Strategies for the Treatment of Acute Myelogenous Leukemia: Differentiation Induction—Present Use and Future Possibilities

Øystein Bruserud, Bjørn Tore Gjertsen

Section for Hematology, Department of Medicine, Haukeland University Hospital; Institute of Anatomy and Cell Biology, University of Bergen, Bergen, Norway

Key Words. Acute myelogenous leukemia • Differentiation • Apoptosis • Immunotherapy

Øystein Bruserud, M.D., Ph.D., Department of Medicine, Haukeland Hospital, N-5021 Bergen, Norway. Telephone: 47-55-29-80-60; Fax: 47-55-97-29-50.


   ABSTRACT
Top
 Abstract
Introduction
 Differentiation Induction in the...
 Differentiation Induction in AML...
 Differentiation Induction and...
 Conclusion
 References
 
A differentiation block and an accumulation of immature myeloid cells characterize acute myelogenous leukemia (AML). However, native AML cells usually show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, for example, all-trans retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment of the acute promyelocytic leukemia (APL) variant of AML. Although several agents can also induce leukemic cell differentiation for other AML subgroups, in vitro studies as well as clinical data have demonstrated that these agents often have heterogeneous effects on the leukemic progenitors. This makes the clinical impact of differentiation induction therapy for individual patients difficult to predict. However, differentiation induction should be regarded as a promising therapeutic approach, especially as a part of immunotherapy or in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. Although the morphology-based French-American-British classification was used to identify APL as an AML subset that required a special treatment, it seems unlikely that this classification alone can be used to identify new subsets of AML patients with special therapeutic requirements. Future studies on differentiation induction in AML should therefore focus on A) the identification of therapeutic agents with more predictable effects; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation induction has a predictable and beneficial effect, and C) the characterization of how AML blast sensitivity to drug-induced apoptosis is altered by differentiation induction.


   INTRODUCTION
Top
 Abstract
 Introduction
Differentiation Induction in the...
 Differentiation Induction in AML...
 Differentiation Induction and...
 Conclusion
 References
 
Acute myelogenous leukemia (AML) is characterized by a neoplastic proliferation of myeloid cells [1-8]. The malignant cells have a differentiation block that results in an accumulation of immature cells, and AML can thus be diagnosed: A) if at least 30% of nucleated cells in the bone marrow are myeloblasts (or alternatively 20%, [8]); B) in the case of bone marrow showing erythroid predominance, if at least 30% of nonerythroid cells are myeloblasts, or C) if the characteristic signs of hypergranular promyelocytic leukemia (acute promyelocytic leukemia, [APL]) are present [1, 2].

Cases of AML can be subclassified on the basis of morphology, cytochemistry, immunological markers, and/or cytogenetics [1-5]. According to the widely accepted French-American-British (FAB) classification, AML can be divided into the following subclasses based on the differentiation of the malignant cells [1-5]: AML-M0 and -M1 show minimal differentiation; AML-M2 includes a minor maturing granulocytic component, whereas AML-M3 (APL) has a dominating accumulation of promyelocytes; AML-M4 and -M5 show myelomonocytic differentiation; AML-M6 has an erythroid predominance; and AML-M7 is the acute megakaryoblastic leukemia. Native AML blasts may also on rare occasions show basophilic or eosinophilic differentiation [6, 7]. These morphological criteria are also incorporated in the recently published World Health Organization classification of myeloid neoplasms [8]. For a subset of AML patients, the leukemia blasts even show functional evidence of differentiation and are capable of antibody-dependent attachment and internalization (phagocytosis) of bacteria as well as zymosane particles [9].

AML treatment usually includes intensive chemotherapy administered as A) induction treatment that aims to bring the patient into complete hematological remission, and B) consolidation therapy that aims to eradicate residual disease and prevent AML relapse [5]. Consolidation therapy with intensive chemotherapy alone or in combination with autologous stem cell transplantation is associated with a relatively high risk of AML relapse and an overall long-term AML-free survival of less than 50%, whereas consolidation with allotransplantation has a lower relapse risk but a higher treatment-related mortality [5]. The addition of differentiation induction therapy with all-trans retinoic acid (ATRA) is now regarded as mandatory in the treatment of APL [10-13], and the use of differentiation induction as a therapeutic approach with low treatment-related morbidity and mortality is also considered for other AML patients.


   DIFFERENTIATION INDUCTION IN THE TREATMENT OF APL
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 Abstract
 Introduction
 Differentiation Induction in the...
Differentiation Induction in AML...
 Differentiation Induction and...
 Conclusion
 References
 
APL is characterized by the expansion of malignant myeloid cells blocked at the promyelocyte stage of differentiation. Several excellent reviews of the pathogenesis, diagnosis, and treatment of APL have recently been published [10-14], and we will only briefly comment on the clinical use of differentiation induction in APL. This AML subset is associated with reciprocal chromosomal translocations that involve the retinoic acid receptor {alpha} (RAR{alpha}) gene on chromosome 17q21 [10, 12, 13]. The RAR{alpha} most commonly fuses to the PML gene on chromosome 15q23, but in rare variants of APL the RAR{alpha} fuses with the promyelocytic leukemia zinc finger gene on chromosome 11q23, the nucleophosmin gene on chromosome 5q32, or the nuclear mitotic apparatus gene on chromosome 11q13. These translocations lead to fusion genes and the expression of aberrant chimeric proteins.

ATRA belongs to the retinoid family of vitamin A derivatives [10-14]. The retinoids exert important effects on cell development, proliferation, and differentiation, and their biological effects are mediated by the RAR and the retinoid X receptors (RXRs). Only the RARs can be activated by ATRA. The molecular mechanisms for the antileukemic effect of ATRA are probably complex and include ligand binding to PML-RAR{alpha} with degradation of fusion proteins and altered transcription regulation [12]. The effects of ATRA seem to differ in the various subsets of APL patients, and patients with t(11;17) have a worse prognosis and little or no effect of ATRA therapy [10, 12, 13].

Effects of ATRA in APL
The in vitro effects of ATRA have been characterized in detail both for AML cell lines (HL60 and NB4 cells) and native APL cells [10, 14]. The presence of ATRA during in vitro culture increases the fraction of differentiated cells with functional characteristics of normal neutrophils. ATRA will also increase cytokine secretion, induce a mature membrane molecule phenotype, inhibit leukemia cell proliferation, and induce apoptosis [14-18].

A number of phase II studies have also confirmed that ATRA induces complete remission and rapid resolution of the life-threatening bleeding complications in a majority of APL patients [10-14, 19], and this in vivo effect seems to be caused by true differentiation of the malignant cells with apoptosis as the final mechanism by which the leukemic clone is extinguished [14, 15, 18].

Induction therapy with ATRA followed by chemotherapy has been compared with chemotherapy alone in two large randomized studies [19, 20], and both studies demonstrated an increased long-term APL-free survival of patients treated with combination therapy. A recent randomized study has also demonstrated that the long-term APL-free survival is higher for patients who receive simultaneous combination therapy compared with sequential combination [21]. The advantage of simultaneous combinations seems to include better control of both the ATRA syndrome and the coagulopathy [10, 21]. In these three studies the chemotherapy was daunorubicin plus cytarabine, but nonrandomized studies suggest that cytarabine may be omitted from induction therapy in APL [22-24].

The recent randomized studies included two cycles of intensive postremission chemotherapy with daunorubicin plus cytarabine without ATRA [20, 21]. It should be mandatory that the consolidation therapy include an anthracycline; the benefit of cytarabine, however, has been questioned [10, 22-24]. APL patients also seem to benefit from some type of additional maintenance treatment that probably should include ATRA [20, 21, 24]. When APL treatment is based on these therapeutic principles, an event-free survival exceeding 75% at 2 years has been described [21].

Arsenic Derivatives as Differentiation-Inducing Agents in APL
In vitro studies have shown that certain arsenic derivatives are effective against APL cells, and a recent clinical study demonstrated that AsO3 should be regarded as a promising therapeutic agent with limited toxicity [25]. This agent seems to act as a differentiation and apoptosis inducer, and the results suggest a possible role of arsenic derivatives in consolidation and/or maintenance therapy [25].


   DIFFERENTIATION INDUCTION IN AML CELLS WITH NON-APL PHENOTYPE
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 Abstract
 Introduction
 Differentiation Induction in the...
 Differentiation Induction in AML...
Differentiation Induction and...
 Conclusion
 References
 
Cytokine Effects on AML Blast Differentiation In Vitro
Although the effects of various cytokines on AML cell (native blasts and AML cell lines) proliferation and viability have been extensively studied, relatively few studies have examined effects of single cytokines, cytokine combinations, or cytokines plus vitamin-D3 on differentiation of native AML blasts [26-34]. Many of these studies are in addition relatively small, and the patients are often heterogeneous with regard to prognostic factors and FAB classification. However, the following conclusions are justified based on the representative studies summarized in Table 1Go: A) AML blasts can be induced to differentiate in several myeloid directions, and the same differentiation response can often be induced by different cytokines [26-34]; B) a certain cytokine or cytokine combination usually induces differentiation only for a subset of patients, and the direction of differentiation often varies between patients [27, 29]; C) differentiation induction can be independent of the effects on blast proliferation, and D) the direction of differentiation often shows no correlation with FAB classification (i.e., previous signs of differentiation) [27, 29-31]. Thus, in contrast to the predictable effects of differentiation induction in APL, the effects in other AML subsets are difficult to predict in individual patients. The same conclusion was also drawn in a clinical study of interleukin 3 (IL-3) therapy in AML [35]. Future investigations of differentiation induction should therefore focus on A) the identification of new agents/combinations/procedures with more predictable effects, and B) the identification of patient subsets in which the effects are predictable and likely to be clinically beneficial.


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  		Table 1. Differentiation induction in human AML cells cultured in vitro in the presence of soluble mediators: a summary of the results from representative studies
 
Candidate Drugs for Differentiation Induction

Cytotoxic Drugs   Anticancer agents (e.g., cytarabine, daunorubicin, 6-thioguanine) can induce differentiation in AML cell lines and in native AML blasts [36-39], and combinations of cytosine arabinoside or 6-thioguanine plus retinoic acid plus either hexamethylene or dimethylformamide seem to induce AML blast differentiation even for a majority of patients [37-39]. This effect is observed at lower concentrations than are required for drug-mediated killing, and it probably involves drug-induced alterations in the cytokine responsiveness of AML cells [36].

Altered Histone Acetylation   Acetylation and deacetylation of histones are regarded as important for transcription activation and repression, respectively. Histone deacetylase inhibitors can induce differentiation in native AML blasts for a subset of patients, and they also cause a synergistic enhancement of ATRA-induced differentiation [40]. These effects show no correlation with previous signs of differentiation (i.e., FAB classification). Butyrates are another group of drugs that seem to induce gene expression via histone hyperacetylation, and monosaccharide butyrate derivatives can also induce differentiation in native AML blasts for a subset of patients [41].

High-Dose Methylprednisolone   Both in vitro and in vivo studies suggest that high-dose methylprednisolone (30 mg/kg/day) can induce differentiation of AML cells to mature granulocytes that subsequently die from apoptosis [42-44]. However, this treatment has been tried only in a few patients, and one should be very careful with the interpretation of these results.

Metal Chelators   In vitro exposure to the metal chelator dithizone will induce differentiation and apoptosis in the AML cell line ML-1 [45]. Although this drug is probably not suitable for clinical use due to its side effects, the results suggest that this new therapeutic approach may become useful in future therapy.

ATRA and Vitamin D3 Analogs   Except for APL, ATRA and vitamin D3 are not potent enough to provide clinical benefit when used at doses that can be tolerated by patients [46]. However, a recent study described that, although addition of ATRA to chemotherapy did not improve patient outcome, in vitro evidence for response to ATRA was detected in 25% of the patients [47]. In vitro studies have also demonstrated that the differentiation induction effects of ATRA, vitamin D3, and/or vitamin D3 derivatives can be enhanced by several other agents [48, 49], including the drug clofibric acid, which has been used without serious side effects in hyperlipemic patients [48]. Thus, combination treatment with chemotherapy, ATRA, and ATRA-potentiating agents may become useful in AML.

Differentiation Induction and Regulation of Apoptosis

Drug-Induced Apoptosis in AML   In vitro studies have demonstrated that apoptosis can be induced in AML blasts by several cytotoxic drugs, including cytarabine [50-54], daunorubicin [54], etoposide [55], idarubicin [56], and 6-thioguanine [51]. Furthermore, clinical studies indicate that the expression of apoptosis-regulating molecules (bcl-2, Mcl-1, caspases) is important for the risk of relapse after chemotherapy [57-59]. Taken together these data suggest that the susceptibility of AML blasts to drug-induced apoptosis is important for the outcome after intensive chemotherapy in AML.

Bcl-2 Levels and Chemosensitivity   Studies of the AML cell line HL-60 have demonstrated that cells induced to differentiate toward neutrophils subsequently die via apoptosis [60]. A possible mechanism for induction of apoptosis is the reduction of the intracellular bcl-2 level, which is observed during differentiation of both HL-60 AML cells and normal myeloid progenitors [61]. There is also an association between high bcl-2 levels in AML cells and decreased sensitivity to drug-induced apoptosis [51-53], and for a subset of patients the inhibition of bcl-2 with antisense oligonucleotides will increase the sensitivity of native blasts to cytarabine-induced apoptosis [50]. This last observation suggests that bcl-2 is directly involved in the regulation of drug-induced apoptosis, possibly via intracellular pathways involving bcl-xL expression [52], prevention of caspase gene expression [55], and/or reduction of oxidant activity by toxic radicals [53]. These results also suggest that differentiation induction therapy may become useful in selected AML patients by increasing the blast sensitivity to drug-induced apoptosis.

The effect of ATRA on differentiation, bcl-2 levels, and chemosensitivity in AML blasts has been studied in AML cell lines. For certain cell lines ATRA can induce differentiation and reduce intracellular bcl-2 levels without altering the susceptibility to drug-induced apoptosis [56, 62]; for other cell lines an increased chemosensitivity seems to depend on G0/G1 cell-cycle arrest rather than the differentiation status or bcl-2 levels [56]; and for a last group of cell lines ATRA seems to increase chemosensitivity by downregulation of bcl-2 [53, 54]. ATRA can also downregulate bcl-2 expression in native AML blasts for a subset of patients independent of their FAB classification [63]. These effects of ATRA on bcl-2 seem to be mediated by different mechanisms, including regulation of transcription, altered phosphorylation, and decreased bcl-2 stability [54, 64]. The effects of ATRA on chemosensitivity can be further modulated by vitamin K analogs; many of these nontoxic analogs induce apoptosis and enhance effects of ATRA via a mechanism involving downregulation of bcl-2 and upregulation of Bax expression with concomitant activation of caspase-3 [65].

A recent study concluded that bcl-2 expression in AML blasts was not an independent prognostic factor in AML patients receiving intensive chemotherapy [66]. This in vivo observation thus seems to conflict with the in vitro results described above. However, the induction and timing of apoptotic events seem to be both cell type and inducer dependent [67], and various cytotoxic drugs seem to use different intracellular pathways for induction of apoptosis [51, 67]. These heterogeneities may explain the apparent discrepancy between the in vitro results and the available clinical data. Future studies therefore have to consider that A) the prognostic impact of high bcl-2 levels may differ between patients, and B) the impact of various prognostic factors (including bcl-2 expression) may also depend on the type of chemotherapy.

Expression of Tumor Suppressor Genes   The p53 tumor suppressor gene is an important regulator of apoptosis in AML blasts [68]. Recent studies suggest that certain conformational variants of p53, which occur either by mutation or by the action of hematopoietic growth factors, permit AML blast survival and are associated with a bad prognosis [69]. Decreased expression of the retinoblastoma tumor suppressor gene in the AML blasts is also associated with an increased risk of leukemia resistance or relapse [70]. Although the expression of both p53 and its negative regulator protein, MDM2, is associated with the differentiation status and is increased in AML blasts with a myelomonocytic phenotype (FAB-types M4/M5) [71], it is not known whether the expression or function of tumor suppressor molecules will be altered by differentiation induction therapy.


   DIFFERENTIATION INDUCTION AND IMMUNOTHERAPY IN AML
Top
 Abstract
 Introduction
 Differentiation Induction in the...
 Differentiation Induction in AML...
 Differentiation Induction and...
Conclusion
 References
 
AML blasts often have genetic abnormalities (e.g., mutations, translocations, inversions [4]) that encode abnormal proteins with leukemia-specific peptide sequences [72]. T cell recognition of such leukemia-specific epitopes has been detected for the t(9;21) (Philadelphia chromosome) and the t(15;17) (APL) translocations [73-75], and these observations support the hypothesis that enhancement of autologous antileukemic T cell reactivity is possible in AML.

Antigen-specific T cell recognition requires the presence of professional accessory cells with a dual function: A) antigenic peptides have to be presented in the context of self-HLA before they can be recognized by specific T cells, and B) antigen-specific T cells need an additional costimulatory signal to become activated; in the absence of costimulation, specific T cell anergy may develop [72, 76]. Dendritic cells are considered as the most potent professional antigen-presenting cells [77]. Although native AML blasts with a phenotype consistent with progenitors of dendritic Langerhans' cells have been described [78], this phenotype seems to be very rare. Native AML blasts usually express only some of the membrane molecules needed for initiation of T cell activation, including the peptide-presenting HLA class I and class II molecules and the T cell binding CD58 molecule, but in most cases the AML blasts do not express the costimulatory B7 (CD80 and CD86) and CD45 molecules [72, 79]. One possible approach for enhancement of AML-specific T cell reactivity would therefore be to induce a dendritic cell phenotype in AML blasts, and thereafter to use these modulated cells for presentation of leukemia-specific antigens to T cells (Table 2Go). In vitro studies have demonstrated that AML blasts can be induced to differentiate into a dendritic cell phenotype by exposure to exogenous cytokines [80-84], and for a subset of patients coculture of autologous T lymphocytes with such AML-derived dendritic cells can induce a leukemia-specific T cell response [80, 82]. This patient heterogeneity is probably caused both by variation in the ability of AML blasts to acquire the dendritic cell phenotype, and by immunogenetic differences that result in T cell nonresponsiveness to leukemia-specific antigens in certain patients [75, 85].


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  		Table 2. Induction of a dendritic cell (DC) phenotype in native AML blasts by exposure to exogenous cytokines; characterization of the experimental in vitro models [80-84]
 

   CONCLUSION
Top
 Abstract
 Introduction
 Differentiation Induction in the...
 Differentiation Induction in AML...
 Differentiation Induction and...
 Conclusion
References
 
At present, differentiation induction therapy is used only in the treatment of the AML-M3/APL subset. Although in vitro studies have demonstrated that leukemia blasts derived from other AML patients may also be induced to differentiate, these effects are difficult to predict in individual patients. Future studies of differentiation induction in AML should therefore try to identify A) new agents or combinations of agents with more predictable effects; B) subsets of patients who are likely to benefit from differentiation induction, and C) cytotoxic drugs that can be used in combination with differentiation induction therapy.


   ACKNOWLEDGMENTS
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 Differentiation Induction in AML...
 Differentiation Induction and...
 Conclusion
 References
 
The study was supported by the Norwegian Cancer Society. The advice of Professor Peter Ernst is gratefully acknowledged.


   REFERENCES
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 Differentiation Induction in AML...
 Differentiation Induction and...
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Received March 1, 2000; accepted for publication March 2, 2000.



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