Understanding Acute Myeloid Leukemia

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
   
Introduction
Examples of Biomarkers in Acute Myeloid Leukemia    
Examples of Blood Markers in Acute Myeloid Leukemia    
Research on Natural Compounds Which May be Suppressive Against Acute Myeloid Leukemia Cell Lines      
Conventional Treatment Options in Acute Myeloid Leukemia      
References

Introduction
Acute myeloid leukemia (AML) is a hematological malignancy that results from transformation of multipotent hematopoietic progenitors and leads to accumulation of immature myeloid cells in the bone marrow.(Pesakhov et al 2010)

Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. (Zuo et al 2010)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

Disease manifestations of AML represent the final common pathway initiated by diverse errors during hematopoiesis and dysfunctional signaling resulting from these errors may result in different transcription factor responses in different patients. Silibinin (an extract of milk thistle) for example, has been found to exhibit a wide spectrum of anticancer activity in various solid tumor models in vitro and in vivo, likely due its ability to target multiple cellular regulatory pathways. Indeed, it has been shown to inhibit growth factor- and cytokine-induced signaling cascades, to modulate the activation of mitogen-activated protein kinases and mTOR, and to suppress different transcription factors, such as NFκB, AP-1, STAT1, STAT3 and STAT5 in tumor cell and tissue preparations. (Zhang et al 2010)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Recent evidence shows that pharmaconutrients may act against proliferation, angiogenesis and metastasis in different types of human cancer. (Granci et al 2010) 

Examples of Biomarkers in Acute Myeloid Leukemia
Alpha- and beta-synucleins – We observed over expression of β-synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that α- and β-synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs. (Maitta et al 2011)

FLT3 (FMS-related tyrosine kinase 3) – Mutations of the FLT3 receptor tyrosine kinase consisting of internal tandem duplications (ITD) have been detected in blasts from 20% to 30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. (Ahmad et al 2010)

Leukemic stem cells (LSCs) – In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML. (Gentles et al 2010)

PARP – The present study has provided evidence that grape seed extract GSE induces human leukemia cell death with the activation of caspases-3, -8, and -9 as well as PARP cleavage, and that GSE-induced apoptosis is proceeded by the activation of JNK and thus up-regulation of Cip1/p21. The data presented here suggest that Cip1/p21 and JNK signaling pathway may represent attractive targets to GSE-induced apoptosis in human leukemia cells. The results of this study could have implications for the incorporation of agents such as GSE into the chemopreventive or therapeutic intervention against leukemia and possibly other hematologic malignancies. (Gao et al 2009)

PI3K/Akt (phosphoinositide 3-kinase) pathway is activated in acute myelogenous leukemia (AML) and is promising for targeted inhibition. Constitutive PI3K/Akt activity is a favorable prognosis factor in AML, even after adjustment for FLT3-ITD, and may confer a particular sensitivity to chemotherapy. A better understanding of the downstream effectors of the PI3K/Akt pathway is needed before targeting in AML. (Tamurini et al 2007)

STAT-3 – We have demonstrated that constitutive signal transducer and activator of transcription (STAT) 3 activity, observed in approximately 50% of acute myeloid leukemia (AML) cases, is associated with adverse treatment outcome. (Gupta et al 2008)

TNFalpha – Tumor necrosis factor (TNF)-alpha and other cytokines are involved in the pathogenesis of acute myeloid leukemia (AML). Higher TNF-alpha levels were found to correlate with poorer performance status; higher leukocyte counts; higher levels of beta2-microglobulin, creatinine, uric acid, and alkaline phosphatase; lower levels of creatinine clearance and albumin; baseline infection; and M4-M5 AML subtypes. (Tsimberidou ete al 2008)TOPO-II alpha – Our results suggest that both beta-catenin and topo IIalpha independently predicted an adverse prognosis and might serve as new markers for risk stratification in AML patients. (Chen et al 2009)

Examples of Blood Markers in Acute Myeloid Leukemia  
Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) – HCT-CI ≥ 3 was the most significant factor for treatment decision making regarding intensity of chemotherapy. The use of standardized comorbidity assessment tools, such as HCT-CI, for elderly patients with AML is practical and can help to improve treatment decision regarding the intensity of chemotherapy. (Djunic et al 2011)LDH and cHSP70 – Levels of cHSP70 showed significant positive correlation with lactate dehydrogenase (LDH) and white blood cells (WBC) in AML and ALL patients, which may reflect overall tumor load. Furthermore, patients with higher levels of cHSP70 had significantly shorter survival in AML (P=0.04) and ALL (P=0.05), suggesting that in these two acute diseases, cHSP70 is an indicator for poor prognosis. Our data support the potential of using free cHSP70 as a biomarker in leukemias and potentially other types of cancers. (Yeh et al 2010)

LDH – The most significant predictor for rate of complete remission in elderly patients with acute myeloid leukemia is serum lactate dehydrogenase (LDH) level, P = 0.049, and the most significant predictor of early death is leucocytosis, P = 0.007. (Djunic et al 2011)
Research on Natural Compounds That May be Suppressive Against Acute Myeloid Leukemia Cell Lines
All of the major signaling pathways, which are deregulated in cancer, and which have been examined as targets for cancer prevention, can be modified by one or more dietary components. These include but are not limited to, carcinogen metabolism, DNA repair, cell proliferation, apoptosis, inflammation, immunity, differentiation and angiogenesis. (Davis et al 2010)

Artemisinin – Artemisinin, the active principle of the Chinese medicinal herb Artemisia annua, and its derivatives (i.e. dihydroartemisinin, DHA) were reported to exhibit anti-tumor activity both in vitro and in vivo. The findings in the present study showed that DHA-induced apoptosis in human leukemia cells in vitro and exhibited an anti-leukemic activity in vivo through a process that involves MEK/ERK inactivation, Mcl-1 down-regulation, culminating in cytochrome c release and caspase activation. (Gao et al 2011)

Curcumin, carnosic acid and silibinin – Here we show that distinct combinations containing potentially bioavailable concentrations of curcumin, carnosic acid and silibinin were selectively toxic or growth inhibitory to human AML cells, without cytotoxicity to normal blood cells or fibroblasts. (Pesakhov et al 2010)Grape seed proanthocyandinin extract – induced mitochondria-associated apoptosis in human acute myeloid leukemia 14.3D10 cells. (Hong & Yi-min 2006) 

Indole-3-carbinol suppressed constitutive NF-kappaB activation in mononuclear cells derived from bone marrow of acute myelogenous leukemia patients, and this correlated with inhibition of cell growth. Overall, our results indicated that indole-3-carbinol inhibits NF-kappaB and NF-kappaB-regulated gene expression and that this mechanism may provide the molecular basis for its ability to suppress tumorigenesis. (Takada et al 2005)

Melatonin increased the apoptotic effects of H(2)O(2) in human myeloid HL-60 cells as assessed by cellular viability, mitochondrial permeability transition induction, mitochondrial membrane depolarization, ROS generation, caspases 3, 8 and 9 activity, phosphatidylserine externalization, and DNA fragmentation techniques. When healthy leucocytes were exposed to H(2)O(2), melatonin increased the viability of the cells. Taken together, the findings indicate that melatonin is a potential physiological tool capable of protecting healthy cells from chemotherapy-induced ROS production as well as inducing tumour cell death. Because cancer cells manifest increased oxidative stress as a result of their elevated metabolism, the use of melatonin may be useful in impairing their ROS buffering capacity. (Bejarano et al 2011)

Parthenolide used in combination with PI3K/mTOR inhibitors – Compared with single agent treatment, exposure of AML cells to the combination of parthenolide and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors significantly decreased viability of AML cells and reduced tumor burden in vitro and in murine xenotransplantation models. (Hassane et al 2010)

Quercetin and genistein – Natural phytoestrogens such as the isoflavones genistein and daidzein, and the flavones quercetin exhibit anti-cancer properties. This study was purposed to investigate the anti-proliferative effect of phytoestrogens on acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cells, and their synergistic antileukemic effect in combination with chemotherapeutic drugs. The results showed that genistein exhibited a dose- and time-dependent inhibitory effect on cell proliferation in NB4 and HL-60 cells, induced apoptosis and cell cycle arrest in G2/M phase. Quercetin had evident inhibitory effect on the proliferation of K562 and K562/A cells. (Chen et al 2008)
Conventional Treatment Options in Acute Myeloid Leukemia
The mainstream approach for AML treatment is intensive combination chemotherapy with cytosine arabinoside (Ara-C) and anthracyclines such as doxorubicin or idarubicin. However, despite initial responses to chemotherapy, prognosis is poor for the majority of AML patients due to primary resistance and frequent relapse. Furthermore, standard treatment is highly toxic and poorly tolerated, particularly by older patients. Thus, the development of novel therapeutic agents and protocols is in an urgent need for improving outcomes in patients with AML. (Pesakhov et al 2010)

Current best treatments utilise anthracyclines e.g. daunorubicin or idarubicin, alongside the pyrimidine and purine analogue cytarabine with or without 6-thioguanine. These drugs non-selectively inhibit DNA and RNA synthesis and consequently their anti-leukaemic activity is associated with high levels of systemic toxicity, including further reduction of haemopoiesis. Although the current therapies of choice, these agents fail to cure more than two thirds of those patients deemed able to tolerate the therapy. The problem is further exacerbated by the molecular heterogeneity underlying the disease as well as its distribution within the population. AML incidence increases with age and >75% of patients are older than 60 years of age at diagnosis. These older patients have a much reduced capacity to tolerate high dose chemotherapy and their leukaemia’s are associated with higher frequencies of unfavourable prognostic factors. (Khanim et al 2009)

Currently, no standard treatment is available for elderly patients with de novo/secondary acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy. New, less aggressive therapies are therefore needed. Histone deacetylase inhibitors (HDACi) are known to reduce proliferation and induce differentiation in hematological malignancies. With all-trans retinoic acid (ATRA) these effects have been reported to be even enhanced. Valproic acid (VPA) is an HDACi and has been known as anti-epileptic agent for many years. Treatment was tolerated well with moderate side effects. 4 patients revealed hematological improvement and another 4 patients experienced a reduction in transfusion dependency. The overall response rate was 27%. (Bellos & Mahlknecht 2008)
References
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Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  20103.  

Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 20014.  

Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008
 
Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006
 
McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002

Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009
 
Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008
 
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Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010

Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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