Implications of the 5th Edition of the World Health Organization Classification and International Consensus Classification of Myeloid Neoplasm in Myelodysplastic Syndrome With Excess Blasts and Acute Myeloid Leukemia
2023; 43(5): 503-507
Ann Lab Med 2022; 42(5): 585-589
Published online September 1, 2022 https://doi.org/10.3343/alm.2022.42.5.585
Copyright © Korean Society for Laboratory Medicine.
Young Eun Lee , M.S.1, Ha Jin Lim , M.D.2, Ju Heon Park , M.D.2, Hye Ran Kim , Ph.D.3, Min-Gu Kang , M.D., Ph.D.4, Young Kuk Cho , Ph.D.5, Jong Hee Shin , M.D., Ph.D.2, and Myung Geun Shin, M.D., Ph.D.1,2
1BioMedical Sciences Graduate Program (BMSGP), Chonnam National University and Chonnam National University Hwasun Hospital, Hwasun, Korea; 2Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Korea; 3College of Korean Medicine, Dongshin University, Naju, Korea; 4Department of Laboratory Medicine, Gwangyang Sarang General Hospital, Gwangyang, Korea; 5Department of Medical Laboratory Science, Seoyeong University, Gwangju, Korea
Correspondence to: Myung Geun Shin, M.D., Ph.D.
Department of Laboratory Medicine, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Jeollanam-do 58128, Korea
Tel: +82-61-379-7950
Fax: +82-61-379-7984
E-mail: mgshin@chonnam.ac.kr
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cytogenetically normal acute myeloid leukemia (CN-AML) accounts for 40%–50% of all AML cases. Despite advances in understanding the molecular pathophysiology of CN-AML, its clinical outcome remains unsatisfactory and unpredictable. To investigate its clinical implication in CN-AML, we measured the expression of prohibitin 2 (PHB2) using immunohistochemical staining (IHCS) of paraffin-embedded bone marrow sections from 134 CN-AML patients. IHCS results were semi-quantitatively scored. Clinical outcome was analyzed in comparison with other prognostic markers, including NPM1 polymorphism and FLT3 internal tandem duplication, and WT1 and BAALC mRNA expression. Except for BAALC mRNA expression, the known molecular markers showed no prognostic effect in the CN-AML patients. PHB2 protein overexpression was significantly associated with adverse prognosis in CN-AML patients. The PHB2 protein expression status may serve as an independent prognostic indicator in CN-AML.
Keywords: Acute myeloid leukemia, Prohibitin 2, Prognosis
Acute myeloid leukemia (AML) is a biologically complex hematopoietic disease characterized by maturation arrest and the expansion of immature cells within the bone marrow (BM). Chromosomal aberrations detected at diagnosis are regarded as the most important factors for predicting the clinical outcome. Conventional cytogenetic analysis at the time of diagnosis provides the most important clinical information in AML patients; however, 40%–50% of patients do not harbor clonal chromosomal aberrations [1]. Most cases of cytogenetically normal AML (CN-AML) are currently categorized in the intermediate-risk group, which is quite heterogeneous [2, 3]. Identifying recurrent molecular abnormalities has improved prognosis and has provided insight into the mechanisms of leukemogenesis in patients with CN-AML, leading to the discovery of novel therapeutic targets [4]. However, many of the polymorphisms and expression patterns identified are still not well understood and require further analysis for determining their exact roles in CN-AML [5].
Recently, several molecular markers that allow the prediction of outcome risk, even in patients with CN-AML, have been identified [6]. The presence or absence of somatically acquired genetic alterations in CN-AML and other cytogenetic groups is currently an important consideration when performing risk assessment in these patients. Following the identification of these polymorphisms, patients with CN-AML are now recognized as a diverse group with distinct clinical outcomes. Both the WHO and European Leukemia Net classify recurrent molecular abnormalities as a complement to cytogenetics [4, 7, 8]. The identification of new molecular markers is an important requirement for the implementation of precision medicine for CN-AML patients.
Prohibitins (PHBs) are ubiquitously expressed in mammalian cells and mediate transcriptional repression through nuclear hormone receptors by recruiting histone deacetylases. They are involved in regulating mitochondrial respiration and aging. PHBs are tumor suppressors and anti-proliferative cell-cycle regulators in normal cells. They are localized in the nucleus, cytosol, and mitochondria and have distinct functions depending on their cellular localization. PHBs are divided into types I and II based on their similarity to yeast PHB1 and PHB2, respectively [9]. PHB alterations have been found in aging and cancer as well as in neurodegenerative, cardiac, and kidney diseases associated with mitochondrial impairments [9]. PHB2 protein expression is aberrantly increased in leukemia cells in BM aspirates of patients with AML at initial diagnosis [10]. This observation prompted us to investigate the clinical implications of PHB2 protein expression in CN-AML.
Between July 2004 and March 2012, 134 patients (males:females, 1:0.87) with CN-AML were enrolled. This study was approved by the Institutional Review Board of Chonnam National University Hwasun Hospital (Hwasun, Korea) (IRB No. 2019-001). Informed consent was obtained from all participating patients (Supplemental Data Table S1). AML was diagnosed according to the 2016 WHO classification criteria; all patients enrolled received intensive remission induction therapy consisting of three days of idarubicin at 12 mg/m2/day and seven days of cytarabine at 100 mg/m2/day or N4-behenoyl-1-D-arabinofuranosylcytosine (300 mg/m2/day for patients younger than 40 years, 200 mg/m2/day for patients older than 40 years). Patients who achieved received three courses of high-dose cytarabine chemotherapy (3 g/m2 every 12 hours/day on days 1, 3, and 5) showed complete remission (CR). All patients had
Survival analysis was performed in comparison with other prognostic factors, including age,
Table 1 shows the OS difference and HRs according to the different PHB2-IHCS score cutoffs. Among all scores (0–8), when we used 6 as a cutoff for PHB2 overexpression, the survival difference between the normal and overexpression groups was the highest (22.3%) and most significant, and the HR was significant (
Table 1 . OS differences and HRs according to different PHB2 IHCS cutoff scores in CN-AML patients
IHCS cutoff* | Survival rate | HR | |||||
---|---|---|---|---|---|---|---|
Normal group (%) | Overexpressing group (%) | OS difference (%) | HR | ||||
1 | 40.0 | 29.1 | 10.9 | 0.864 | 1.06 (0.53–2.11)† | 0.864 | |
2 | 43.5 | 27.5 | 16.0 | 0.373 | 1.31 (0.73–2.35) | 0.374 | |
3 | 42.9 | 26.9 | 16.0 | 0.212 | 1.41 (0.82–2.41) | 0.214 | |
4 | 44.8 | 26.1 | 18.7 | 0.130 | 1.51 (0.88–2.59) | 0.133 | |
5 | 46.9 | 25.1 | 21.8 | 0.052 | 1.67 (0.99–2.84) | 0.055 | |
6 | 44.7 | 22.5 | 22.3 | 0.031# | 1.64 (1.04–2.58) | 0.033# | |
7 | 32.9 | 27.0 | 5.9 | 0.417 | 1.18 (0.79–1.78) | 0.416 | |
8 | 31.6 | 20.0 | 11.6 | 0.092 | 1.68 (0.92–3.08) | 0.094 |
*The IHCS cutoff was scored on a scale of 0–8, the sum of a diffuseness score (0–5), and an intensity score (0–3) [1]; #
Abbreviations: OS, overall survival; HR, hazard ratio; IHCS, immunohistochemical staining; PHB2, prohibitin 2; CN-AML, cytogenetically normal acute myeloid leukemia.
PHB is vital in tumorigenesis and tumor progression. However, its molecular role in cancer development has not been fully elucidated. Mitochondrial PHBs (mainly PHB2) are overexpressed in leukemia cells and promote cell survival under oxidative stress [11]; however, the clinical implications thereof remained unclear. This result was consistent with ours that PHB2 is highly expressed in BM CN-AML cells. CN-AML patients with higher PHB2 expression in their AML cells showed worse OS than CN-AML patients having relatively lower PHB2 protein expression.
PHB protein levels are significantly higher in tumor cells isolated from patients with leukemia and lymphoma than in PB mononuclear cells from healthy donors. Concordant with PHB expression observed in tumor cell lines, PHB is overexpressed in primary lymphoid and myeloid tumor cells [11]. These results suggest that PHBs are upregulated during tumorigenesis to maintain mitochondrial integrity; they may serve as novel biomarkers and molecular targets for therapeutic intervention of certain types of hematologic malignancies [11].
The molecular mechanisms underlying effects of PHB2 in promoting cell migration have not been fully elucidated. Shen,
In conclusion, PHB2 protein overexpression was associated with inferior OS in CN-AML patients. Assessing PHB2 protein expression in CN-AML using IHCS is a feasible approach to predicting disease activity and prognosis and may provide clinically useful information for the diagnosis, prognosis, and detection of minimal residual disease in CN-AML patients.
None.
Shin MG designed the study. Lee YE, Lim HJ, and Park, JH enrolled the patients, collected the clinical laboratory data, and performed the laboratory measurements. Shin MG and Lee YE drafted the manuscript. Shin MG, Park JH, Lee YE, Kang, MG, and Kim HR analyzed the data and revised the manuscript. Cho YK and Shin JH provided valuable comments and recommendations. All authors revised and accepted the final version of the manuscript.
No potential conflicts of interest relevant to this article were reported.
This research was supported by National Research Foundation of Korea grants funded by Ministry of Science and ICT (MSIT) (No. 2019R1F1A1059859) and the Ministry of Education (No. 2018R1D1A1B07040984).