APOPTOSIS DEREGULATIONS IN MYELODYSPLASTIC SYNDROMES
Keywords:
myelodysplastic syndrome, refractory anemia, acute myeloid leukemia, hemopoietic stem cells, apoptosis, cytokines, growth factors, chemokines, prognostic factors.Abstract
Summary. The purpose of the review is to analyze modern ideas about the role and mechanisms of apoptotic cell death in patients with myelodysplastic syndromes (MDS). Numerous data suggest that apoptosis (Ap) is involved in dysplastic and ineffective
hemopoiesis and neoplastic bone marrow (BM) transformation in MDS. While the level of Ap cells of BM increases with the development of MDS, the suppression
of Ap in MDS patients increases the likelihood of developing acute myeloid leukemia. This article summarizes the latest data on the role of Аp in the pathogenesis of
MDS, as well as information on the prognostic and predictive role of cellular apoptotic markers, the levels of
a number of cytokines, growth factors and chemokines
in MDS patients. Particular attention is paid to such effectors of apoptosis as the death receptors, proteins of the
BCL-2 family and the IAP family, the c-FLIP adapter
proteins, tumor protein p53.
References
SEER Cancer Statistics Review, 1975-2015, National Cancer
Institute. Bethesda, MD, Noone AM, Howlader N, Krapcho M,
et al., eds. Section 30. Myelodysplastic syndromes (MDS), chronic myeloproliferative disorders (CMD) and chronic myelomonocytic leukemia (CMML). https://seer.cancer.gov/csr/1975_2015/.
Cartwright RA, Alexander FE, McKinney PA, Ricketts TJ.
Myelodysplastic states. In: Leukaemia and Lymphoma. An atlas
of leukaemia and lymphoma distribution within areas of England
and Wales (1984–1988). London: Leukaemia Research Fund,
: 32–40.
Aul C, Gattermann N, Schneider W. Age-related incidence
and other epidemiological aspects of myelodysplastic syndromes.
Br J Haematol 1992; 82 (2): 358–67.
Rådlund A, Thiede T, Hansen S, et al.Incidence of myelodysplastic syndromes in a Swedish population. Eur J Haematol 1995;
(3): 153–6.
Maynadié M, Verret C, Moskovtchenko P, et al. Epidemiological characteristics of myelodysplastic syndrome in a well-defined
French population. Br J Cancer 1996; 74 (2): 288–90.
Intragumtornchai T, Prayoonwiwat W, Swasdikul D, et al. Myelodysplastic syndromes in Thailand: a retrospective pathologic and
clinical analysis of 117 cases. Leuk Res 1998; 22 (5): 453–60.
Chihara D, Ito H, Katanoda K, et al. Incidence of myelodysplastic syndrome in Japan. J Epidemiol 2014; 24 (6): 469–73.
Aul C, Giagounidis A, Germing U. Epidemiological features
of myelodysplastic syndromes: results from regional cancer surveys
and hospital-based statistics. Int J Hematol 2001; 73 (4): 405–10.
Strom SS, Vélez-Bravo V, Estey EH. Epidemiology of myelodysplastic syndromes. Semin Hematol 2008; 45 (1): 8–13.
Du Y, Fryzek J, Sekeres MA, Taioli E. Smoking and alcohol
intake as risk factors for myelodysplastic syndromes (MDS). Leuk
Res 2010; 34 (1): 1–5.
Strom SS, Gu Y, Gruschkus SK, et al. Risk factors of myelodysplastic syndromes: a case-control study. Leukemia 2005; 19
(11): 1912–8.
Lv L, Lin G, Gao X, et al. Case-control study of risk factors
of myelodysplastic syndromes according to World Health Organization classification in a Chinese population. Am J Hematol 2011;
(2): 163–9.
Gluzman DF, Sklyarenko LM, Koval SV, et al. Myelodysplastic syndromes and ionizing radiation. Oncology 2014; 16 (1):
–4 (in Russian).
Kesminiene A, Evrard AS, Ivanov VK, et al. Risk of hematological malignancies among Chernobyl liquidators. Radiat Res
; 170 (6): 721–35.
Marsden K, Challis D, Kimber R. Familial myelodysplastic
syndrome with onset late in life. Am J Hematol 1995; 49 (2): 153–6.
West AH, Godley LA, Churpek JE. Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for
translational investigations. Ann N Y Acad Sci 2014; 1310: 111–8.
Smith RE, Bryant J, DeCillis A, et al. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National
Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 2003; 21 (7): 1195–204.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to
the World Health Organization classification of myeloid neoplasms
and acute leukemia. Blood 2016; 127 (20): 2391–405.
Greenberg PL, Stone RM, Al-Kali A, et al. Myelodysplastic
Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in
Oncology. J Natl Compr Canc Netw 2017; 15 (1): 60–87.
Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 2018; 25 (3): 486–541.
Perini GF, Ribeiro GN, Pinto Neto JV, et al. BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol
; 11 (1): 65.
Mohamed MS, Bishr MK, Almutairi FM, Ali AG. Inhibitors of apoptosis: clinical implications in cancer. Apoptosis 2017;
(12): 1487–509.
Testa U. TRAIL/TRAIL-R in hematologic malignancies. J
Cell Biochem 2010; 110 (1): 21–34.
Tognon R, Nunes Nde S, Castro FA. Apoptosis deregulation in
myeloproliferative neoplasms. Einstein (Sao Paulo) 2013; 11 (4): 540–4.
Brinkmann K, Kashkar H. Targeting the mitochondrial apoptotic pathway: a preferred approach in hematologic malignancies?
Cell Death Dis 2014; 5: e1098.
Fulda S. Inhibitor of apoptosis (IAP) proteins in hematological malignancies: molecular mechanisms and therapeutic opportunities. Leukemia 2014; 28 (7): 1414–22.
Zaman S, Wang R, Gandhi V. Targeting the apoptosis pathway
in hematologic malignancies. Leuk Lymphoma 2014; 55 (9): 1980–92.
Droin N, Guéry L, Benikhlef N, Solary E. Targeting apoptosis proteins in hematological malignancies. Cancer Lett 2013; 332
(2): 325–34.
Saha MN, Micallef J, Qiu L, Chang H. Pharmacological activation of the p53 pathway in haematological malignancies. J Clin
Pathol 2010; 63 (3): 204–9.
Hatfill SJ, Fester ED, Steytler JG. Apoptotic megakaryocyte dysplasia in the myelodysplastic syndromes. Hematol Pathol
; 6 (2): 87–93.
Yoshida Y. Hypothesis: apoptosis may be the mechanism responsible for the premature intramedullary cell death in the myelodysplastic syndrome. Leukemia 1993; 7 (1): 144–6.
Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis,
proliferation, and the Bcl-2-related proteins in the myelodysplastic
syndromes and acute myeloid leukemia secondary to MDS. Blood
; 96 (12): 3932–8.
Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered
oncoprotein expression and apoptosis in myelodysplastic syndrome
marrow cells. Blood 1996; 88: 4275–87.
Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E, et al.
Apoptosis in patients with myelodysplastic syndromes: differential
involvement of marrow cells in ‘good’ versus ‘poor’ prognosis patients and correlation with apoptosis-related genes. Leukemia 1999;
: 1554–63.
Bogdanović AD, Trpinac DP, Janković GM, et al. Incidence
and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment. Leukemia 1997; 11 (5): 656–9.
Raza A, Gezer S, Mundle S, et al.Apoptosis in bone marrow
biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 1995; 86: 268–76.
Philchenkov AA. Apoptosis-reactivating agents for targeted anticancer therapy. Biomedical Chemistry 2013; 59 (2): 119–
(in Russian).
Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-alpha, Fas and Fas-ligand in marrow failure
associated with myelodysplastic syndrome. Br J Haematol 1998;
(1): 176–88.
Maciejewski J, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34+ human marrow cells is induced by inter-
feron gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood 1995;
: 3183–90.
Meyers CA, Albitar M, Estey E. Cognitive impairment, fatigue, and cytokine levels in patients with acute myelogenous leukemia or myelodysplastic syndrome. Cancer 2005; 104 (4): 788–93.
Allampallam K, Shetty V, Hussaini S, et al. Measurement of
mRNA expression for a variety of cytokines and its receptors in bone
marrows of patients with myelodysplastic syndromes. Anticancer Res
; 19 (6B): 5323–8.
Gupta P, Niehans GA, LeRoy SC, et al. Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates
with FAB subtype and anemia, and predicts survival. Leukemia
; 13 (1): 44–53.
Sawanobori M, Yamaguchi S, Hasegawa M, et al. Expression of TNF receptors and related signaling molecules in the bone
marrow from patients with myelodysplastic syndromes. Leuk Res
; 27 (7): 583–91.
Zang DY, Goodwin RG, Loken MR, et al. Expression of tumor necrosis factor-related apoptosis-inducing ligand, Apo2L, and
its receptors in myelodysplastic syndrome: effects on in vitro hemopoiesis. Blood 2001; 98 (10): 3058–65.
Schenk RL, Strasser A, Dewson G. BCL-2: Long and winding path from discovery to therapeutic target. Biochem Biophys Res
Commun 2017; 482 (3): 459–69.
Boudard D, Vasselon C, Berthéas MF, et al. Expression and
prognostic significance of Bcl-2 family proteins in myelodysplastic
syndromes. Am J Hematol 2002; 70 (2): 115–25.
Jilg S, Reidel V, Müller-Thomas C, et al.Blockade of BCL-2
proteins efficiently induces apoptosis in progenitor cells of high-risk
myelodysplastic syndromes patients. Leukemia 2016; 30 (1): 112–23.
Philchenkov A, Miura K. The IAP protein family, SMAC
mimetics and cancer treatment. Crit Rev Oncog 2016; 21 (3–4):
–202.
Yamamoto K, Abe S, Nakagawa Y, et al. Expression of IAP
family proteins in myelodysplastic syndromes transforming to overt
leukemia. Leuk Res 2004; 28 (11): 1203–11.
Safa AR, Pollok KE. Targeting the anti-apoptotic protein
c-FLIP for cancer therapy. Cancers (Basel) 2011; 3 (2): 1639–71.
Benesch M, Platzbecker U, Ward J, et al. Expression of
FLIP(Long) and FLIP(Short) in bone marrow mononuclear and
CD34+ cells in patients with myelodysplastic syndrome: correlation
with apoptosis. Leukemia 2003; 17 (12): 2460–6.
Kopnin BP, Kopnin PB, Khromova NV, et al. Multifaced
р53: variety of forms,functions, tumor-suppressive andoncogenic
activities. Clinical Oncohaematology 2008; 1 (1): 2–9 (in Russian).
Kurotaki H, Tsushima Y, Nagai K, Yagihashi S. Apoptosis, bcl-2 expression and p53 accumulation in myelodysplastic syndrome, myelodysplastic-syndrome-derived acute myelogenous leukemia and de novo acute myelogenous leukemia. Acta Haematol
; 102 (3): 115–23.
Saft L, Karimi M, Ghaderi M, et al. p53 protein expression independently predicts outcome in patients with lower-risk
myelodysplastic syndromes with del(5q). Haematologica 2014; 99
(6): 1041–9.
Hollstein M, Hergenhahn M, Yang Q, et al. New approaches to understanding p53 gene tumor mutation spectra. Mutat Res
; 431 (2): 199–209.
Pellagatti A, Boultwood J. The molecular pathogenesis of
the myelodysplastic syndromes. Eur J Haematol 2015; 95 (1): 3–15.
Zhang L, Padron E, Lancet J. The molecular basis and clinical significance of genetic mutations identified in myelodysplastic
syndromes. Leuk Res 2015; 39 (1): 6–17.
Gañán-Gómez I, Wei Y, Starczynowski DT, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia 2015; 29 (7): 1458–69.
Keith T, Araki Y, Ohyagi M, et al. Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming
to overt leukaemia. Br J Haematol 2007; 137 (3): 206–15.
Bagby GC, Jr. Interleukin-1 and hematopoiesis. Blood Rev
; 3 (3): 152–61.
Dinarello CA. Biologic basis for interleukin-1 in disease.
Blood 1996; 87 (6): 2095–147.
Pardanani A, Finke C, Lasho TL, et al. IPSS-independent
prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes. Leukemia 2012; 26 (4): 693–9.
Liu M, Guo S, Stiles JK. The emerging role of CXCL10
in cancer (review). Oncol Lett 2011; 2 (4): 583–9.
Tsimberidou AM, Estey E, Wen S, et al. The prognostic significance of cytokine levels in newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndromes. Cancer 2008; 113
(7): 1605–13.
Kastrinaki MC, Pavlaki K, Batsali AK, et al. Mesenchymal
stem cells in immune-mediated bone marrow failure syndromes.
Clin Dev Immunol 2013; 2013: 265608.
Zhao Z, Wang Z, Li Q, et al.The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or
high-risk myelodysplastic syndromes. PLoS One 2012; 7 (9): e45675.
Jöhrer K, Ploner C, Thangavadivel S, et al. Adipocyte-derived players in hematologic tumors: useful novel targets? Expert
Opin Biol Ther 2015; 15 (1): 61–77.
Berezhnaya NM, Chekhun VF. Immunology of malignant
growth. Kiev: Naukova Dumka, 2005. 791 p. (in Russian).
