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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 39  |  Issue : 2  |  Page : 72-79

Study of the role of HSP90 in acute myeloid leukemia


1 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, USA
2 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, USA

Date of Submission09-Feb-2014
Date of Acceptance01-Apr-2014
Date of Web Publication30-Aug-2014

Correspondence Address:
Sahar M Hazza
Professor of Clinical Pathology, Moderyia Str. Teba Tower, Nhail Lab., Tanta
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.139769

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  Abstract 

Review Heat shock proteins (HSPs) are a group of proteins whose expression are increased when the cells are exposed to elevated temperature or other stress. This increase in expression is transcriptionally regulated. A member of HSP family is HSP90, it is expressed in cytoplasm of most human cells.HSP90 exists in two forms HSP90 alpha, inducible and HSP90B, constitutive. HSP90 has a more restricted repertoire of client proteins mainly including protein kinase. It seems to be important for cellular proliferation, survival and adaptation to unfavorable microenvironments, and HSP90 inactivation results in inappropriate functioning and rapid degradation of its client proteins. Its normal chaperoning activity is strongly dependent on its co-chaperones, i.e. accessory proteins that interact with HSP90 and induce conformational changes.
Aim The work was conducted to to evaluate the role of HSP90 in acute myeloid leukemia and find out its impact on prognosis.
Subject and Method The subjects of this study were 90 patients with acute myeloid leukemia. The age of patients ranged from 4-67 years with a mean value of 43.367 ±15.146 years. They were 66 (73.33%) males, and 24 (26.67%) females. After diagnosis patients received chemotherapy and they were followed up for periods of 18 months with special attention to clinical and laboratory markers of remission and relapse and estimation of ate of first complete remission, date of relapse, death or last seen alive.
Results In the current study, 90 newly diagnosed acute myeloid leukemic patients were investigated for HSP90 expression. High expression of HSP90 (>20%) was found in 48/90 (53.33%) AML patients and low expression of HSP90 (<20%) was found in 42/90 of patients (46.67%). In the current work, the age of selected patients ranged from 4-67 years with mean age of 43 years. In present study, it was found that 66/90 AML patients (73.33%) were males and 24/30 AML patients (26.67%) were females. Among the newly diagnosed AML patients; 43.33% had hepatomegaly, 50% had lymphadenopathy, 50% had pallor, 40% had purpura, and 60% had splenomegaly. There was no correlation between HSP90 expression and clinical features. As regard hematological finding, there was no significant association between HSP90 and Hb level. The present study showed mild to severe thrombocytopenia in almost all AML patients, There was no association between platelet count and HSP90 expression. There was a significant association of high total leucocytic count with high HSP90 expression. Circulating blasts in peripheral blood and blasts in BM were significantly associated with high expression of HSP90 in AML patients compared to low expressed HSP90 cases. There was statistically non significant relation between HSP90 expression and FAB subtype. There was a statistically significant association between high HSP90 expression and bad prognosis including relapse or death while the high remission rates were associated significantly with low expression of HSP90 cases.

Keywords: HSP90, Acute myeloid leukemia Prrognosis


How to cite this article:
Hazza SM, Azzat AA, El Shora OA, El-Bedwey MM. Study of the role of HSP90 in acute myeloid leukemia . Egypt J Haematol 2014;39:72-9

How to cite this URL:
Hazza SM, Azzat AA, El Shora OA, El-Bedwey MM. Study of the role of HSP90 in acute myeloid leukemia . Egypt J Haematol [serial online] 2014 [cited 2019 Dec 11];39:72-9. Available from: http://www.ehj.eg.net/text.asp?2014/39/2/72/139769


  Introduction Top


Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of myeloid progenitor cells that gradually replace normal hematopoiesis in the bone marrow (BM). The genetic changes arising in the neoplastic clone lead to cascades of molecular events that cause abnormal proliferation, aberrant differentiation, and inhibition of normal hematopoiesis by the malignant cells [1] .

Heat shock proteins (HSPs) are molecular chaperones for protein molecules. They are usually cytoplasmic proteins and they perform functions in various intracellular processes. They play an important role in protein-protein interaction such as folding and assisting in the establishment of proper protein conformation (shape) and prevention of unwanted protein aggregation. By helping to stabilize partially unfolded proteins, HSPs aid in transporting proteins across membranes within the cell [2] .

HSPs are a group of proteins whose expression are increased when the cells are exposed to elevated temperature or other stress. This increase in expression is transcriptionally regulated. This marked upregulation of the HSPs is induced mostly by heat shock factor. Their production can also be triggered by exposure to different kinds of environmental stress conditions such as infection, inflammation, and exposure of the cell to toxins [3] .

A member of HSP family is HSP90; it is expressed in cytoplasm of most human cells. HSP90 exists in two forms: HSP90a, inducible, and HSP90β, constitutive [4] .

HSP90 has a more restricted repertoire of client proteins mainly including protein kinase. It seems to be important for cellular proliferation and survival and adaptation to unfavorable microenvironments, and HSP90 inactivation results in inappropriate functioning and rapid degradation of its client proteins. Its normal chaperoning activity is strongly dependent on its cochaperones - that is, accessory proteins that interact with HSP90 and induce conformational changes [5] .

High levels of HSP90 expression have been reported in many types of cancer cells [6] .

The study was conducted to evaluate the role of HSP90 in AML and to find out its impact on prognosis.


  Patients and methods Top


The participants of this study were 90 patients with AML. The age of patients ranged from 4 to 67 years with a mean value of 43.367 ± 15.146 years. There were 66 (73.33%) male patients and 24 (26.67%) female patients. All patients were attendant of Hematology/Oncology Unit, Pediatrics and Internal Medicine Department, Tanta University Hospitals.

Patients were studied at first diagnosis and were previously untreated. The diagnosis of AML was assessed by morphological study and cytochemistry of peripheral blood (PB) and BM samples according to the French Amercian British (FAB) classification of acute leukemia and by immunophenotyping.

After diagnosis, patients received chemotherapy and they were followed up for periods of 18 months with special attention to clinical and laboratory markers of remission and relapse and to estimation of date of first complete remission (CR), date of relapse, death, or last seen alive.

Patients were judged to have achieved CR when BM aspirates showed trilineage regeneration with less than 5% blasts by morphologic and immunocytochemical analysis, in the presence of normal blood count that persisted for at least 1 month. All other patients were considered nonresponsive [7] .

Immunophenotyping was carried out on PB or BM samples on EDTA using Becton Dickinson FAC Scan flow cytometry (Becton Dickinson, San Jose, California, USA) with panels of monoclonal antibodies stained with either fluorescein isothiocyanate or phycoerythrin including B-lymphoid markers (CD10, CD19, CD20), T-lymphoid markers (CD2, CD3, CD7), myeloid and monocytic markers (CD13, CD33, CD117, CD14, CD64), and megakaryocytic (CD61) and erythroid markers (glycophorin A). These markers were supplied by Becton Dickinson (Heidelberg, Germany).

Analysis of heat shock protein 90

Expression of HSP90 by blast cells from PB or BM samples of patients was measured using flow cytometry. A volume of 450 μl of lysing fluid was applied to 100 μl of sample. It was mixed well by vortex then incubated for 10 min at room temperature. Then, 500 μl of washing solution (PBS) was added and centrifuged at 3000 rpm for 5 min. The supernatant was discarded. A volume of 500 μl of permeabilizing reagent was added to each tube, mixed well by vortex, and incubated for 10 min at room temperature. Tubes were centrifuged at 3000 rpm for 5 min and supernatant was discarded, and then washed once with PBS. Thereafter, 10 μl of negative control was added to control tube and 10 μl of phycoerythrin-labeled anti-HSP90 monoclonal antibody was added to other tube. Tubes were mixed well by vortex then incubated for 30 min at 2-8°C. They were washed twice using PBS then the supernatant was discarded after each wash. Then 0.5 ml of PBS was added to be ready for acquisition. Flow cytometry data were analyzed using the Cell Quest Software (Cell Quest software, BD, version 3, verity software House Topsham, ME, USA). A total of 10 000 events were acquired and gating was performed using forward scatter and side scatter, and percentage of positivity was calculated.

The case was considered high HSP90 expression, if HSP90 percent was equal to or exceeded the cutoff of 20%, and it was considered low HSP90 expression if HSP90 percent was less than 20%.

Statistical analyses

Data were analyzed using SPSS (version 16; SPSS Inc., Chicago, Illinois, USA). Quantitative data were expressed in the form of mean ± SD and qualitative data were described in the form of number and percentage. Differences between groups were evaluated with the t-test. The survival analysis was carried out according to Kaplan-Meier product limit estimates.


  Results Top


This study was carried out on 90 newly diagnosed AML patients, 24 (26.67%) of them were female patients and 66 (73.33%) were male patients. Their ages ranged from 4 to 67 years with the mean value of 43.367 ± 15.146 years. Clinically, of the 90 newly diagnosed patients, 39 (43.33%) patients had hepatomegaly and 45 (50%) patients had lymphadenopathy. There were 45 (50%) patients with pallor, 36 (40%) patients with purpura, and 54 (60%) patients with splenomegaly [Table 1] and [Figure 1].
Table 1: Clinical characteristics of acute myeloid leukemia patients

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Figure 1: Clinical characteristics of acute myeloid leukemia patients.

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Heat shock protein 90 expression

In the present study, high expression of HSP90 (with cutoff value ≥20) was detected in 48/90 (53.33%) patients. Of them, 12 were female patients and the other 36 were male patients; the remaining patients 42/90 (46.67%) showed low expression of HSP90 (<20%) (12 were female patients and the other 30 were male patients). HSP90 expression showed no significant relationship with sex (P > 0.05) in studied AML patients [Table 2].
Table 2: Association of patients' sex and heat shock protein 90 expression

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Comparison between the HSP90 high expression and HSP90 low expression groups regarding clinical data of studied AML patients showed nonsignificant differences (P > 0.05) [Table 3].
Table 3: Comparison between the heat shock protein 90 high expression and heat shock protein 90 low expression groups regarding clinical data of studied acute myeloid leukemia patients

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Comparison between laboratory data in the high and low HSP90 expression groups showed significant increase in total leucocytic count (TLC) and peripheral and BM blasts (P < 0.05) [Table 4].
Table 4: Relationship between laboratory data of studied acute myeloid leukemia patients and heat shock protein 90 expression

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FAB subtype among acute myeloid leukemia patients

Among the studied AML patients, six (6.687%) were diagnosed as M0, 18 (20.06%) as M1, 24 (26.06%) as M2, nine (10.03%) as M3, 12 (13.37%) as M4, and 21 (23.4%) as M5 [Table 5].
Table 5: Relationship between FAB subtype in studied acute myeloid leukemia patients and heat shock protein 90 expression

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The frequency of high HSP90 expression with respect to each FAB subtype was 12 (13.373%) in AML-M1 patients, 12 (13.373%) in AML-M2 patients, six (6.687%) in AML-M3 patients, six (6.687%) in AML-M4 patients, and 12 (13.373%) in AML-M5 patients.

The frequency of low HSP90 expression with respect to each FAB subtype was six (6.687%) in AML-M0 patients, six (6.687%) in AML-M1 patients, 12 (13.373%) in AML-M2 patients, three (3.343%) in AML-M3 patients, six (6.687%) in AML-M4 patients, and nine (10.03%) in AML-M5 patients.

There was statistically nonsignificant relationship between HSP90 expression and FAB subtype [Table 5].

Clinical outcome of the studied acute myeloid leukemia patients

Regarding response to therapy, 15/90 (16.67%) patients showed good response to therapy and achieved CR when assessed on day 14 and day 28 until the end of the study, whereas the remaining 75/90 (83.33%) patients showed poor response to therapy, either developed relapse, induction failure, or even died after short period following the start of therapy.

With respect to prognosis among AML patients with low expression of HSP90 and AML patients with high expression of HSP90, the results were as following:

Clinical remission was achieved in nine (10%) patients with high expression of HSP90 expression, whereas it was achieved in 36 (40%) patients with low HSP90 expression.

Relapse occurred in 21 (23.33%) patients with high expression of HSP90 expression, whereas it occurred in six (6.67%) patients with low expression of HSP90.

Death occurred in 18 (20%) patients with high expression of HSP90, whereas no one died of AML patients with low expression of HSP90.

There was a statistically significant association between high HSP90 expression and bad prognosis including relapse or death, whereas the high remission rates were associated significantly with low expression of HSP90 in AML patients [Table 6] and [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6].
Table 6: Relationship between heat shock protein 90 expression in acute myeloid leukemia patients and their
prognosis


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Figure 2: Relationship between heat shock protein 90 expression in acute myeloid leukemia patients and their prognosis.

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Figure 3: Impact of heat shock protein 90 (HSP90) expression on overall survival (OS) in acute myeloid leukemia patients. Higher HSP90 correlated with reduced OS.

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Figure 4: Impact of heat shock protein 90 (HSP90) expression on disease-free survival (DFS) in acute myeloid leukemia patients. Higher HSP90 expression correlated with reduced DFS.

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Figure 5: Dot blot shows low expression of heat shock protein 90 (HSP90).

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Figure 6: Dot blot shows high expression of heat shock protein 90 (HSP90).

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  Discussion Top


AML has the lowest survival rate of all leukemias [8] . Hence, assessment of the prognostic factors in AML is very important [9] .

Nearly all leukemia-associated antigens are critically involved in important mechanisms responsible for tumor growth, such as proliferation, inhibition of apoptosis, and differentiation, in addition to demethylation [10] . Thus, leukemia-associated antigens play a dual role in the battle against AML blasts: they are specifically expressed or overexpressed by AML cells to increase proliferation and tumor growth, and they are recognized by the immune system that kills AML cells and reduces the leukemia burden. The balance between these two modes of action might be responsible for the correlation between leukemia-associated antigens expression and disease prognosis [11] .

Antitumor immunity can contribute significantly to the control of AML as evidenced by the curative potential of allogenic stem cell transplantation. A number of proteins have been proposed as potential targets for the active immunotherapy of AML [12] . HSPs are stress proteins that are induced by heat shock, ischemia, and various other stressors. They are usually cytoplasmic proteins, and they perform functions in various intracellular processes. They play an important role in protein-protein interaction such as folding and assisting in the establishment of proper protein conformation [2].

Each member of this superfamily of proteins appears to have a distinct set of functions within the cell. These proteins, found in both cancer cells and normal cells, may be referred to as 'molecular chaperones' because of their ability to stabilize proteins and polypeptides, and may function in the signal transduction pathways of different cell regulators. Abnormal HSP expression has been identified as one of the deregulating factors in cellular development. HSPs may be implicated in apoptosis regulation [13] .

HSPs are of special clinical interest because of data suggesting that they may play a role in drug resistance [14].

In the current study, 90 newly diagnosed AML patients were investigated for HSP90 expression. High expression of HSP90 (>20%) was found in 48/90 (53.33%) AML patients and low expression of HSP90 (<20%) was found in 42/90 (46.67%) of patients. This was in agreement with the study by Reikvam et al. [15] who reported that high expression of HSP90 in 98 newly diagnosed AML patients was found in 51% of patients.

However, Cornillon et al. [4] reported that the percentage of highly expressed HSP90 cells was 55% and Flandrin et al. [16] found that the percentage of high expression of HSP90 cells was 41%.

In the current study, the age of selected patients ranged from 4 to 67 years with mean age of 43 years.

There was no significant association between HSP90 and age. This was in contrast with the study by Fredly et al. [17] who found that patient age showed a significant correlation with HSP90, and the elderly patients above 70 years of age showed significantly lower HSP90 levels.

In present study, it was found that 66/90 (73.33%) of AML patients were male and 24/30 (26.67%) were female.

Among the newly diagnosed AML patients, 43.33% had hepatomegaly, 50% had lymphadenopathy, 50% had pallor, 40% had purpura, and 60% had splenomegaly. These results were in agreement with the findings of Schoch et al. [18] who reported that palpable splenomegaly occurs in most AML patients.

With respect to the clinical features of AML patients, hepatomegaly was detected in 27 (30%) AML patients with high expression of HSP90 and in 12 (13.33%) AML patients with low expression of HSP90. There was no significant association between HSP90 expression and hepatomegaly.

Lymphadenopathy was present in 18 (20%) AML patients with high expression of HSP90 and in 27 (30%) AML patients with low expression of HSP90. No significant association between lymphadenopathy and HSP90 expression was detected.

Purpura was noticed in 27 (30%) AML patients with high expression of HSP90 and in nine (10%) AML patients with low expression of HSP90. HSP90 expression showed no significant relationship with purpura in AML patients.

Pallor was noted in 30 (33.33%) AML patients with high expression of HSP90 and in 15 (16.67%) AML patients with low expression of HSP90. HSP90 expression showed no significant relationship with pallor in AML patients.

Splenomegaly was detected in 36 (33.33%) AML patients with high expression of HSP90 and in 18 (16.67%) AML patients with low expression of HSP90. HSP90 expression showed no significant relationship with splenomegaly in AML patients.

These results were in agreement with the study by Flandrin et al. [16] in which no correlation was detected between HSP90 expression and clinical features.

With respect to hematological finding, hemoglobin level was low in most AML patients and ranged from 4.6 to 13 with a mean value of 8.98 ± 1.72 gm/dl. There was no significant association between HSP90 and hemoglobin level. In addition, the present study showed mild to severe thrombocytopenia in almost all AML patients, and thrombocytopenia was manifested frequently with bleeding manifestations. These results were consistent with the study by Zhou et al. [19] in which no association was detected between platelet count and HSP90 expression.

The current study showed the relationship of total leukocytic count with HSP90 expression. There was a significant association of high total leukocytic count with high HSP90 expression. High total leukocytic count was associated with bad prognosis; these results were in accordance with the study by Thomas et al. [20] and Flandrin et al. [16] who noted that elevated total leukocytic count was often associated with poor outcome, but the results were in contrast with the study by Reikvam et al. [15] who reported that no correlation was observed between HSP90 and white blood cell counts.

Circulating blasts in PB and blasts in BM were significantly associated with high expression of HSP90 in AML patients compared with low expressed HSP90 patients. These findings were in agreement with the findings of Fredly et al. [17] and Cornillon et al. [4] who reported significant correlation between the level of circulating blasts and high HSP90 expression.

Among the studied AML patients, six (6.687%) were diagnosed as M0, 18 (20.06%) as M1, 24 (26.06%) as M2, nine (10.03%) as M3, 12 (13.37%) as M4, and 21 (23.40%) as M5.

The frequency of high HSP90 expression with respect to each FAB subtype was M1 in 12 (13.373%) AML patients, M2 in 12 (13.373%) AML patients, M3 in six (6.687%) AML patients, M4 in six (6.687%) AML patients, and M5 in 12 (13.373%) AML patients.

The frequency of low HSP90 expression with respect to each FAB subtype was M0 in six (6.687%) AML patients, M1 in six (6.687%) AML patients, M2 in 12 (13.373%) AML patients, M3 in three (3.343%) AML patients, M4 in six (6.687%) AML patients, and M5 in nine (10.03%) AML patients. There was statistically nonsignificant relationship between HSP90 expression and FAB subtype. Contradictory results were reported by Thomas et al. [20] and Fredly et al. [17] who found that HSP90 was significantly correlated to FAB subtype. In this respect, Thomas et al. [20] found that HSP90 was highly expressed in FAB M5 cytological subtype.

With respect to chemotherapeutic response, there was significant association between HSP90 and chemotherapeutic resistance; CR was achieved in three (10%) patients with high expression of HSP90, whereas it was achieved in 36 (40%) patients with low expression of HSP90, which was in agreement with the study by Flandrin et al. [16] and Thomas et al. [20] .

Relapse occurred in 21 (23.33%) patients with high expression of HSP90, whereas it occurred in six (6.67%) patients with low expression of HSP90.

Death occurred in 18 (20%) patients with high expression of HSP90, whereas no one of AML patients with low expression of HSP90 died.

There was a statistically significant association between high HSP90 expression and bad prognosis including relapse or death, whereas the high remission rates were associated significantly with low expression of HSP90 in AML patients. This was in agreement with the study by Thomas et al. [21] and Kornblau et al. [21] who reported that significant correlation was observed between the expression of HSP90 and that of other markers associated with poor prognosis and resistance to chemotherapy. They also reported that intracellular overexpression of HSP90a/b was observed in poor-prognosis AML cells, indicating that HSP90 has a role in cell survival and resistance to chemotherapy.

It was found that patients with high HSP90 expression showed shorter overall survival time and shorter disease-free survival (DFS) time when compared with patients with low HSP90 expression.

Similar observations on overall survival of the patients were reported by Thomas et al. [20] who found that overall survival was significantly longer in patients with lower expression of HSP90 than in those displaying a high expression of HSP90.

In this respect, Flandrin et al. [16] found that the overall survival was significantly longer in patients with low HSP90 expression than in patients with high HSP90 expression.

Flandrin et al. [16] also conducted a study on DFS and reported that DFS in the 45 patients in remission was a trend for longer DFS in patients with low HSP90 levels.

Cornillon et al. [4] reported that higher HSP90 levels, as assessed by flow cytometry, were associated with a poor prognosis and higher expression of activated signal transduction proteins - phosphoinositide 3-kinase (PI3K), phosphoserine-threonine protein kinase (AKT), and other extracellular signal-regulated kinases - necessary for maintenance of oncoproteins such as BCR-ABL, mutated C-kit, and FLT3.

In this study, increased expression of HSP90 at diagnosis was significantly associated with laboratory prognostic factors such as higher white blood cell count and higher blast percentage in PB and in BM, and also with adverse outcome. These findings were consistent with the results published by Thomas et al. [21] and Fredly et al. [17].

Holler et al. [22] also demonstrated that HSP90 plays an essential role in AML invasion, metastasis and angiogenesis, apoptosis, and necrosis.

HSP90 plays a role in the process of tissue invasion and metastasis by acting on its client proteins such as urokinase, in addition to its role in limitless replicative potential by stabilizing telomerase [23].

It evades apoptosis by acting on IGF and AKT; it also has a great role in sustained angiogenesis by stabilizing VEGF, MET, and RTKs, and in insensitivity to antigrowth signals by stabilizing CDK4, CDK6, and cyclin [24].

The high HSP90 expressed cells in AML patients display strong capability of tumor resistance to chemotherapy and predict bad therapeutic outcomes. In addition, the present data indicated that high HSP90 expression can be rapidly and easily determined at disease presentation. The HSP90 expression, therefore, should be incorporated into the initial laboratory work-up and risk-stratified treatment strategies for all newly diagnosed AML patients.

Study of HSP90 in cancer at the cell and molecular level, although promising, is still in its infancy, and we currently have little information on how HSP90 regulation is subverted in cancer and how HSP90 dysregulation affects tumor growth, invasiveness, and metastasis. Such studies will be essential in interpreting and targeting HSP90 in cancer therapy.

HSP90 may be useful in early diagnosis of AML and may be introduced in immune therapy.


  Acknowledgements Top


 
  References Top

1.Suhag VS, Soloman SR, Malkovska V. Acute myelogenous leukemia (chapter 11). In: Rogers G, Young N, editors. The Bethesda handbook of clinical hematology. 2nd ed. Philadelphia, USA: Lippincott Williams & Wilkins; 2010.131-136.  Back to cited text no. 1
    
2. 2 Mosser DD, Richard I. Molecular chaperones and the stress of oncogenesis. Oncogene 2004; 23: 2906-2918.  Back to cited text no. 2
    
3. 3 Hartle FU, Hayer-Hartle M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 2002; 295 :1852-1858.  Back to cited text no. 3
    
4. 4 Cornillon J, Flandrin P, Tavernier E, Nadal N, Morteux F, Solly F, et al. Heat shock protein 90 is overexpressed in high risk myelodysplastic syndromes and associated with higher expression and activation of focal adhesion kinase. Oncotarget 2012; 3 :1158-1168.  Back to cited text no. 4
    
5. 5 Wandinger SK, Richter K, Buchner J. The Hsp90 chaperone machinery. J Biol Chem 2008; 283 :18473-18477.  Back to cited text no. 5
    
6. 6 Leskovar A, Wegele H, Werbeck ND, Buchner, J, Reinstein J. The ATPase cycle of the mitochondrial Hsp90 analog Trap1. J Biol Chem. 2008; 283 :11677-11688.  Back to cited text no. 6
    
7. 7 Nozomi N, Okabe-Kado J, Michihiro N, Naoki W, Akiko S, Nobuo M, et al. Plasma level of the differentiation inhibitory factor nm-H1 protein and their clinical implication in acute myelogenous leukemia. Blood 2000; 96: 1080-1086.  Back to cited text no. 7
    
8. 8 Redaelli A, Lee MJ, Stephen MJ, Pashos LC. Epidemiology and clinical burden of acute myeloid leukemia. Expert Rev Anticancer Ther 2003; 5 :695-710.  Back to cited text no. 8
    
9. 9 Phekoo KJ, Richards MA, Moller H, Schey SA. The incidence and outcome of myeloid malignancies in 2112 adult patients in southeast England. Haematologica 2006; 91 :1400-1404.  Back to cited text no. 9
    
10.10 Greiner J, Bullinger L, Guinn B, Döhner H, Schmitt M. Leukemia-associated antigens are critical for the proliferation of acute myeloid leukemia cells. Clin Cancer Res 2008; 14 : 7161-7166.  Back to cited text no. 10
    
11.11 Zhang L, Greiner J. Leukemia-associated antigens are immunogenic and have prognostic value in acute myeloid leukemia. Immunotherapy 2011; 3 :697-699.  Back to cited text no. 11
    
12.12 Greiner J, Schmitt M, Li L, Gannopoulos K, Bosch K, Schmitt A, et al. Expression of tumor associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood 2006; 108: 4109-4117.  Back to cited text no. 12
    
13.13 Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B. Role of human heat shock protein 70 HSP70 in protection against stress induced apoptosis. Mol Cell Biology 1997; 17 :5317-5327.  Back to cited text no. 13
    
14.14 Ciocca DR, Fuqua SAW, Lock-Lim S, Toft DO, Welch WJ, McGuire WL. Response of human breast cancer cells to heat shock and chemotherapeutic drugs. Cancer Res 1992; 52 :3648-3654.  Back to cited text no. 14
    
15.15 Reikvam H, Ersvaer E, Bruserud O. Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. Curr Cancer Drug Targets 2009; 9 :761-776.  Back to cited text no. 15
    
16.16 Flandrin P, Guytot D, Duval A. Heat-shock protein (HSP) 90 expression in acute myeloid leukemic cells. Cell Stress Chaperones 2008; 13: 357-364.  Back to cited text no. 16
    
17.17 Fredly H, Reikvam, H, Gjertsen BT, Bruserud O. Disease stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: serum Hsp70 and Hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment. Am J Hematol 2012; 87 :368-376.  Back to cited text no. 17
    
18.18 Schoch C, Kohlmann A, Schnittger S, Brors B, Dugas M, Mergenthaler S, et al. Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles. Proc Natl Acad Sci USA 2002; 99 :10008-10013.  Back to cited text no. 18
    
19.19 Zhou Y, Li Q, Meng HX, Wang YF, Yu Z, Qiu LG. The expression and clinical significance of early differentiation antigens in acute leukemia. Leukemia 2005; 44 :46-49.  Back to cited text no. 19
    
20.20 Thomas X, Campos L, Mounier C, Cornillon J, et al. Expression of heat shock proteins is associated with major adverse prognostic factors in AML. Leuk Res 2005; 29 :1049-1058.  Back to cited text no. 20
    
21.21 Thomas X, Campos L, Mounier C, Cornillon J, Piselli S, Viallet A, Guyotat D. Expression of heat-shock proteins (HSPs) is associated with major adverse prognostic factors in acute myeloid leukemia (AML). Leuk Res 2005; 29 :1049-1058.  Back to cited text no. 21
    
22.22 Holler E, Spacek M, Sedlackova L, Imryskova Z, Hromadnikova I. Heat shock protein expression in leukemia. Tumor Biol 2011; 32 :33-44.  Back to cited text no. 22
    
23.23 Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci 2007; 32: 517-530.  Back to cited text no. 23
    
24.24 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.  Back to cited text no. 24
    


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