НАРУШЕНИЯ АПОПТОЗА ПРИ МИЕЛОДИСПЛАСТИЧЕСКИХ СИНДРОМАХ
Ключові слова:
миелодиспластический синдром, рефрактерная анемия, острый миелоидный лейкоз, гемопоэтические стволовые клетки, апоптоз, цитокины, факторы роста, хемокины, прогностические факторы.Анотація
Цель обзорной статьи — проанализировать современные представления
о роли и механизмах апоптотической гибели клеток у больных при миелодиспластических синдромах (МДС). Многочисленные данные свидетельствуют, что апоптоз (Ап) вовлечен в диспластический и неэффективный
гемопоэз и неопластическую трансформацию клеток костного мозга (КМ)
при МДС. В то время как уровень Ап клеток КМ возрастает при развитии МДС, подавление Ап у больных МДС повышает вероятность развития острого миелоидного лейкоза. В статье представлены последние данные о роли Ап в патогенезе МДС, а также информация о прогностической
и предиктивной роли клеточных апоптотических маркеров, уровня ряда
цитокинов, факторов роста и хемокинов у пациентов с МДС. Особое внимание уделено таким эффекторам Ап, как «рецепторы смерти», белки семейств BCL-2 и IAP, адапторные белки группы c-FLIP, белок-супрессор
опухолевого роста p53.
Посилання
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).
