The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment.

Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells.

The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.

Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis.

Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML.

Two acute myeloid leukemia patient subsets are identified based on the constitutive PI3K-Akt-mTOR signaling of their leukemic cells; a functional, proteomic, and transcriptomic comparison.

OBJECTIVES: Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. The aim of the study was to compare constitutive PI3K-Akt-mTOR activation of primary AML cells for a large group of unselected patients. METHODS: We investigated expression and phosphorylation of 18 mediators in the PI3K-Akt-mTOR main track by flow cytometry for AML cells derived from 77 patients, and compared this with global gene expression profiles, proteomic, and transcriptomic profiles, and susceptibility to antileukemic agents. RESULTS: Patients were divided into two main subsets showing generally high or low constitutive pathway activation. The high activation subset was characterized by decreased frequency of cells showing monocytic differentiation, increased frequency of adverse karyotypes, decreased constitutive cytokine release, and increased expression of certain integrins. Finally, the two groups differed in their expression of genes encoding regulators of protein phosphorylation, whereas phosphoproteomic analyses showed differences especially with regard to transcriptional regulation. Antiproliferative effects of pathway inhibition were generally stronger for the low phosphorylation subset. CONCLUSION: The constitutive PI3K-Akt-mTOR activation differed between patients; this difference appears to be a part of complex phenotypic differences including cell communication, intracellular signaling through other pathways, and transcriptional regulation.

Cytokines, Adhesion Molecules, and Matrix Metalloproteases as Predisposing, Diagnostic, and Prognostic Factors in Venous Thrombosis.

The inflammatory response is a well-established part of, and a prerequisite for, venous thrombosis. To better understand the pathophysiology of venous thrombosis and to identify improved diagnostic biomarkers, further studies of the relationship between inflammation and coagulation are needed. We review previous studies concerning inflammatory biomarkers in venous thromboembolism, in particular cytokines, soluble adhesion molecules and matrix metalloproteases as predisposing, diagnostic and prognostic factors in venous thrombosis. Elevated cytokines and genetic alterations coding for cytokines are found in several patient cohorts which indicate that cytokines are involved as predisposing factors in venous thrombosis development. Increased levels of pro-inflammatory cytokines are detected both in animal models and in patients with acute venous thrombosis and clinical trials, although currently without evident diagnostic value. Adhesion molecules are crucial in the development of venous thrombosis, especially P-selectin seems important in initiating leukocyte accumulation and adhesion to endothelium for subsequent platelet accumulation. Several studies have demonstrated increased soluble P-selectin levels in patients with venous thrombosis, emphasizing its potential role as diagnostic marker and also as a therapeutic target. Matrix metalloproteases are essential effectors during venous thrombosis resolution and may impact vessel wall fibrosis, and together with their natural occurring inhibitors are crucial in acute and chronic thrombosis pathophysiology. Furthermore, studies in animal models of venous thrombosis have demonstrated anti-inflammatory treatment to be effective in terms of thrombus resolution and reduction of vessel wall damage, without increase in bleeding risk during the course of treatment. Thus, soluble mediators should be further investigated both as possible biomarkers and therapeutic targets in venous thromboembolic disease.

Resistance to the Antiproliferative In Vitro Effect of PI3K-Akt-mTOR Inhibition in Primary Human Acute Myeloid Leukemia Cells Is Associated with Altered Cell Metabolism.

Constitutive signaling through the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in acute myeloid leukemia (AML) cells. However, AML is a heterogeneous disease, and we therefore investigated possible associations between cellular metabolism and sensitivity to PI3K-Akt-mTOR pathway inhibitors. We performed non-targeted metabolite profiling to compare the metabolome differences of primary human AML cells derived from patients susceptible or resistant to the in vitro antiproliferative effects of mTOR and PI3K inhibitors. In addition, the phosphorylation status of 18 proteins involved in PI3K-Akt-mTOR signaling and the effect of the cyclooxygenase inhibitor indomethacin on their phosphorylation status was investigated by flow cytometry. Strong antiproliferative effects by inhibitors were observed only for a subset of patients. We compared the metabolite profiles for responders and non-responders towards PI3K-mTOR inhibitors, and 627 metabolites could be detected. Of these metabolites, 128 were annotated and 15 of the annotated metabolites differed significantly between responders and non-responders, including metabolites involved in energy, amino acid, and lipid metabolism. To conclude, leukemia cells that are susceptible or resistant to PI3K-Akt-mTOR inhibitors differ in energy, amino acid, and arachidonic acid metabolism, and modulation of arachidonic acid metabolism alters the activation of mTOR and its downstream mediators.

Patients with acute myeloid leukemia can be subclassified based on the constitutive cytokine release of the leukemic cells; the possible clinical relevance and the importance of cellular iron metabolism.

OBJECTIVE: Acute myeloid leukaemia (AML) is a heterogeneous malignancy; we studied how the constitutive cytokine release by the AML cells varies among patients. METHODS: We investigated the constitutive release of 28 mediators during in vitro culture for 79 consecutive patients. RESULTS: Constitutive cytokine release profiles differed among patients, and hierarchical clustering identified three subsets with high, intermediate and low release, respectively. The high-release subset showed high levels of most mediators, usually monocytic differentiation as well as altered mRNA expression of proteins involved in intracellular iron homeostasis and molecular trafficking; this subset also included 4 out of 6 patients with inv(16). Spontaneous in vitro apoptosis did not differ among the subsets. For the high-release patients, cytokines were released both by CD34+ and CD34- cells. The mRNA and released protein levels showed statistically significant correlations only for eleven of the cytokines. The overall survival after intensive anti-leukemic therapy was significantly higher for high-release compared with low-release patients. Pharmacological targeting of iron metabolism (iron chelation, transferrin receptor blocking) altered the cytokine release profile. CONCLUSIONS: Subclassification of AML patients based on the constitutive cytokine release may be clinically relevant and a part of a low-risk (i.e. chemosensitive) AML cell phenotype.

Mesenchymal Stem Cells Support Survival and Proliferation of Primary Human Acute Myeloid Leukemia Cells through Heterogeneous Molecular Mechanisms.

Acute myeloid leukemia (AML) is a bone marrow malignancy, and various bone marrow stromal cells seem to support leukemogenesis, including osteoblasts and endothelial cells. We have investigated how normal bone marrow mesenchymal stem cells (MSCs) support the in vitro proliferation of primary human AML cells. Both MSCs and primary AML cells show constitutive release of several soluble mediators, and the mediator repertoires of the two cell types are partly overlapping. The two cell populations were cocultured on transwell plates, and MSC effects on AML cells mediated through the local cytokine/soluble mediator network could thus be evaluated. The presence of normal MSCs had an antiapoptotic and growth-enhancing effect on primary human AML cells when investigating a group of 51 unselected AML patients; this was associated with increased phosphorylation of mTOR and its downstream targets, and the effect was independent of cytogenetic or molecular-genetic abnormalities. The MSCs also supported the long-term proliferation of the AML cells. A subset of the patients also showed an altered cytokine network with supra-additive levels for several cytokines. The presence of cytokine-neutralizing antibodies or receptor inhibitors demonstrated that AML cells derived from different patients were heterogeneous with regard to effects of various cytokines on AML cell proliferation or regulation of apoptosis. We conclude that even though the effects of single cytokines derived from bone marrow MSCs on human AML cells differ among patients, the final cytokine-mediated effects of the MSCs during coculture is growth enhancement and inhibition of apoptosis.

Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells.

INTRODUCTION: Midostaurin is a multikinase inhibitor that inhibits receptor tyrosine kinases (Flt3, CD117/c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor 2) as well as non-receptor tyrosine kinases (Frg, Src, Syk, Protein kinase C). Combination of midostaurin with conventional intensive chemotherapy followed by one year maintenance monotherapy was recently reported to improve the survival of acute myeloid leukemia (AML) patients with Flt3 mutations. Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies; (ii) published articles describing the importance of midostaurin-inhibited kinases for leukemogenesis and chemosensitivity. Expert opinion: Midostaurin monotherapy is well tolerated, combined with conventional chemotherapy gastrointestinal toxicity increases significantly. Midostaurin alters anthracycline pharmacokinetics. Furthermore, its antileukemic effects may not only be mediated through Flt3 inhibition alone; the inhibition of other kinases may also be important for the overall antileukemic effect. Midostaurin may then have direct effects on the leukemic cells but also indirect antileukemic effects through inhibition of the AML-supporting effects of neighboring stromal cells in the bone marrow microenvironment. Midostaurin may thus be used in combination with intensive chemotherapy, as maintenance treatment or as disease-stabilizing treatment for elderly unfit patients.

Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia.

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.

Connexin expression in human acute myeloid leukemia cells: identification of patient subsets based on protein and global gene expression profiles.

Bone marrow stromal cells support both normal and malignant hematopoiesis. Τhis support is mediated through the local cytokine network and by direct cell­cell interactions mediated via adhesion molecules and the formation of gap junctions by connexins. Previous studies on connexins in human acute myeloid leukemia (AML) have mainly focused on the investigation of leukemia cell lines. In the present study, we therefore investigated the expression of various connexins at the protein (i.e., cell surface expression) and mRNA level in primary human AML cells. The cell surface expression of the connexins, Cx26, Cx32, Cx37, Cx43 and Cx45, varied considerably between patients, and detectable levels were observed only for subsets of patients. On the whole, Cx43 and Cx45 showed the highest cell surface expression. Connexin expression was dependent on AML cell differentiation, but showed no association with cytogenetic abnormalities or mutations of the fms-related tyrosine kinase 3 (FLT3) or nucleophosmin (NPM)­1 genes. By contrast, only Cx45 showed a significant variation between patients at the mRNA level. A high Cx45 expression was associated with the altered regulation of the mitogen­activated protein kinase (MAPK) pathway and the release of pro-inflammatory cytokines [interleukin (IL)­17, tumor necrosis factor (TNF), interferon­Î³], whereas a low Cx45 expression was associated with the altered regulation of protein functions (i.e., ligase activity, protein folding and catabolism). There was no significant correlation observed between the connexin mRNA and protein levels. Thus, differences in connexin expression can be used to subclassify AML patients. Differences in connexin cell surface expression profiles are not reflected at the mRNA level and have to be directly examined, whereas variations in Cx45 mRNA expression are associated with differences in cell signaling and the regulation of protein functions.

STAT3 as a possible therapeutic target in human malignancies: lessons from acute myeloid leukemia.

STAT3 is important for transcriptional regulation in human acute myeloid leukemia (AML). STAT3 has thousands of potential DNA binding sites but usually shows cell type specific binding preferences to a limited number of these. Furthermore, AML is a very heterogeneous disease, and studies of the prognostic impact of STAT3 in human AML have also given conflicting results. A more detailed characterization of STAT3 functions and the expression of various isoforms in human AML will therefore be required before it is possible to design clinical studies of STAT3 inhibitors in this disease, and it will be especially important to investigate whether the functions of STAT3 differ between patients. Several other malignancies also show extensive biological heterogeneity, and the present discussion and the suggested scientific approaches may thus be relevant for other cancer patients.

Heat shock protein 70 - the next chaperone to target in the treatment of human acute myelogenous leukemia?

INTRODUCTION: Heat shock proteins (HSPs) are molecular chaperones that stabilize folding and conformation of mature proteins. HSPs are, therefore, considered as possible therapeutic targets in the treatment of human cancers, including acute myeloid leukemia (AML). This strategy offers the possibility of targeting several oncogenic proteins or several intracellular signaling pathways through the use of a single therapeutic agent. AREAS COVERED: Several specific HSP70 inhibitors have now been developed. We describe: i) the molecular structure of HSP70 and the molecular interactions especially with its co-chaperones; ii) the immunoregulatory functions of HSP70; iii) the expression and function of HSP70 in human AML cells; iv) the molecular and pharmacological characteristics of potential HSP70 inhibitors; and v) the clinical and experimental studies of HSP70 inhibition in human AML. Our review is based on careful selection of relevant publications identified in the PubMed database. EXPERT OPINION: HSP70 inhibitors have antileukemic activity in human AML. However, additional experimental studies using in vitro models as well as animal models are required, including detailed toxicology studies, as a scientific basis for the optimal design of future clinical studies.

Comparison of in vitro responses to fresh whole blood and reconstituted whole blood after collagen stimulation.

BACKGROUND: In patients who have large bleeds, there is a tendency to transfuse more plasma and platelets than recommended in earlier guidelines, and accordingly many hospitals now provide "transfusion packages" with an intended red cell:platelet:plasma ratio of 1:1:1. The purpose of this study was to investigate in vitro functions of transfusion packs compared with fresh whole blood. MATERIAL AND METHODS: "Reconstituted whole blood" was prepared with the same ratio of red cells, platelets and plasma as used in local transfusion packages. The aggregation and thrombin-antithrombin complex formation responses to collagen stimulation of this reconstituted whole blood were compared with those of fresh whole blood. The storage time of red cells and platelets was varied in a systematic manner, giving nine different compositions of reconstituted whole blood that simulated transfusion packs. RESULTS: The responses varied significantly between whole blood and reconstituted whole blood -and between the reconstituted whole blood of different compositions. A significant decrease (p<0.005) in collagen-induced platelet count reduction was seen with increasing platelet and red blood cell age. Thrombin-antithrombin complex formation peaked in studies with platelets stored for 5 days. The red cells stored for the longest time induced the greatest thrombin-antithrombin complex formation. Fresh whole blood gives more consistent responses, and the aggregation response to collagen is stronger than in reconstituted whole blood. DISCUSSION: Our results indicate that in vitro responses of reconstituted whole blood vary substantially according to how long the red cells and platelets are stored for. As the responses obtained by testing whole blood are more consistent and usually stronger, the alternative use fresh whole blood in special conditions should not be excluded without further consideration.

Predicting effects of kinase inhibitor in therapy for myeloid malignancies - the challenges in capturing disease heterogeneity.

Protein kinase inhibitors have proved to be effective and well tolerated in special form of malignant diseases in which targeted kinases play a central role in the development and progression of the malignant clone. In addition, the development of acquired drug resistance, due to new mutations or clonal evolution, during treatment is common. Methods for measuring the activity and predicting the efficacy of such compounds are warranted for evaluating individual responses to treatment, particularly in a context of widespread preclinical and clinical studies of protein kinase inhibitors in patients with heterogeneous myeloid malignancies.

Pharmacological targeting of the PI3K/mTOR pathway alters the release of angioregulatory mediators both from primary human acute myeloid leukemia cells and their neighboring stromal cells.

Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with poor overall survival. Constitutive as well as cytokine-initiated activation of PI3K/Akt/mTOR signaling is a common feature of AML patients, and inhibition of this pathway is considered as a possible therapeutic strategy in AML. Human AML cells and different stromal cell populations were cultured under highly standardized in vitro conditions. We investigated the effects of mTOR inhibitors (rapamycin and temsirolimus) and PI3K inhibitors (GDC-0941 and 3-methyladenin (3-MA)) on cell proliferation and the constitutive release of angioregulatory mediators by AML and stromal cells. Primary human AML cells were heterogeneous, though most patients showed high CXCL8 levels and detectable release of CXCL10, Ang-1, HGF and MMP-9. Hierarchical clustering analysis showed that disruption of PI3K/Akt/mTOR pathways decreased AML cell release of CXCL8-11 for a large subset of patients, whereas the effects on other mediators were divergent. Various stromal cells (endothelial cells, fibroblasts, cells with osteoblastic phenotype) also showed constitutive release of angioregulatory mediators, and inhibitors of both the PI3K and mTOR pathway had anti-proliferative effects on stromal cells and resulted in decreased release of these angioregulatory mediators. PI3K and mTOR inhibitors can decrease constitutive cytokine release both by AML and stromal cells, suggesting potential direct and indirect antileukemic effects.

Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors.

BACKGROUND: Heat shock proteins (HSPs) are molecular chaperones that assist proteins in their folding to native structures. HSP90, and more recently HSP70, have emerged as possible therapeutic targets in human malignancies, including acute myeloid leukemia (AML). DESIGN AND METHODS: The authors investigated the effects of the HSP70 inhibitor VER-155008 tested alone or in combination with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) on proliferation, viability, constitutive cytokine release and intracellular HSP levels of primary human AML cells. RESULTS: VER-155008 caused a dose-dependent inhibition of cytokine-dependent AML cell proliferation both in suspension cultures and in a colony formation assay, and the drug also had a proapoptotic effect. HSP70 and HSP90 inhibition had additive antiproliferative and proapoptotic effects. VER-155008 caused a strong inhibition of the constitutive AML cell release of several growth factors/regulators of hematopoiesis (i.e., TNF-α, VEGF, IL-3, IL-1ß, IL-1 receptor antagonist), but had relatively weak effects on the constitutive chemokine release. HSP70 inhibition did not induce any compensatory increase of other HSPs. CONCLUSION: HSP70 inhibition has antileukemic effects when tested alone, and the combination of HSP70 and HSP90 inhibition seems to have additive antileukemic effects for primary human AML cells in vitro.

Inhibition of Mammalian target of rapamycin in human acute myeloid leukemia cells has diverse effects that depend on the environmental in vitro stress.

Effects of the mTOR inhibitor rapamycin were characterized on in vitro cultured primary human acute myeloid leukemia (AML) cells and five AML cell lines. Constitutive mTOR activation seemed to be a general characteristic of primary AML cells. Increased cellular stress induced by serum deprivation increased both mTOR signaling, lysosomal acidity, and in vitro apoptosis, where lysosomal acidity/apoptosis were independent of increased mTOR signaling. Rapamycin had antiproliferative and proapoptotic effects only for a subset of patients. Proapoptotic effect was detected for AML cell lines only in the presence of serum. Combination of rapamycin with valproic acid, all-trans retinoic acid (ATRA), and NF-κB inhibitors showed no interference with constitutive mTOR activation and mTOR inhibitory effect of rapamycin and no additional proapoptotic effect compared to rapamycin alone. In contrast, dual inhibition of the PI3K-Akt-mTOR pathway by rapamycin plus a PI3K inhibitor induced new functional effects that did not simply reflect a summary of single drug effects. To conclude, (i) pharmacological characterization of PI3K-Akt-mTOR inhibitors requires carefully standardized experimental models, (ii) rapamycin effects differ between patients, and (iii) combined targeting of different steps in this pathway should be further investigated whereas combination of rapamycin with valproic acid, ATRA, or NF-κB inhibitors seems less promising.

Targeting of polo-like kinases and their cross talk with Aurora kinases--possible therapeutic strategies in human acute myeloid leukemia?

INTRODUCTION: Five human polo-like kinases (PLKs) have been identified, and PLK1 - 4 seem to interact with Aurora kinases and act as cell cycle regulators in both normal and malignant human cells. AREAS COVERED: The present review describes i) experimental evidence for a role for PLKs and Aurora kinases in human leukemogenesis and ii) the results from clinical studies of PLK and Aurora kinase inhibitors in the treatment of human acute myeloid leukemia (AML). The review was based on searches in the PubMed and the ClinicalTrials.gov databases. These inhibitors have antiproliferative and proapoptotic effects in AML cells. Hematological and gastrointestinal toxicities are frequently dose limiting, and this may limit the use of these agents in combination with conventional AML therapy. Aurora kinase inhibitors seem to be most effective for patients with high expression of the target kinases, and the same may be true for PLK inhibitors. EXPERT OPINION: PLK inhibition is a promising strategy for the treatment of AML. Future clinical studies have to clarify i) whether this strategy is most effective for certain subsets of patients; ii) whether multikinase inhibitors targeting several cell cycle regulators should be preferred; and iii) how this therapeutic strategy eventually should be combined with conventional antileukemic chemotherapy.