Kök hücre biyolojisi ve hematolojik malignitelerde kök hücrenin rolü

Yunus Terzi; Şefik Güran

Kök hücre biyolojisi ve hematolojik malignitelerde kök hücrenin rolü

Yıl 2012, Cilt: 34 Sayı: 2, 235 - 241, 21.06.2012

Yunus Terzi , Şefik Güran

Öz

Özet

Kanser, hücrelerin anormal şekilde farklılaşma ve kontrolsüz olarak çoğalması ile karakterize önemli bir hastalık grubudur. Genellikle sadece kanser kök hücresi denen tek bir hücreden köken alır. Tümör hücrelerinin hızlı çoğalması, kanser kök hücrenin kendi kendini yenileyebilme özelliğinden dolayıdır. Kanser kök hücrelerinin tümör oluşumunda önemine rağmen, tümör dokusunda sayıları son derece azdır. Kanser kök hücre biyolojisi hakkında en fazla bilgiye lösemilerde sahibiz. Lösemi, hematopoitetik kanser kök hücresinden köken alan lökositlerin kontrolsüz çoğalması ile tanımlanan kan sisteminin malign bir hastalığıdır. Birçok farklı lösemide kanser kök hücreleri ile normal hematopoietik kök hücrelerinin farklılaşmaları aşamasında elde edilen moleküler değişiklikler, normal ve patolojik hücre farklılaşması arasındaki farkları ortaya koymaktadır. Lösemilerde değişik farklılaşma aşamalarında hücrelerin farklı yüzey markırlarının (belirteçlerinin) tanımlanması aynı farklılaşma aşamasında olan kök hücrelerin tanınmasının yolunu açmıştır. Tüm bu veriler lösemi kök hücrelerinin transformasyon ve farklılaşma süreçlerinin daha iyi anlaşılmasında kullanılmaktadır. Aynı zamanda ksenotransplantasyon çalışmaları ile aynı aşamadaki lösemi kök hücreleri kullanılarak farklı lösemi tiplerine sahip fare modelleri oluşturulmuştur. Bu fare modelleri ile yapılan çalışmalar sonucunda tanımlanan yeni moleküler belirteçler lösemi hastalarının tanısı ve prognozun belirlenmesinde kullanılabilecek bilgi ve bulgular vermektedir. Lösemi kök hücre biyolojisinin anlaşılması, kanserde hedefe doğrudan yapılan kemoterapi yöntemlerinin geliştirilmesinde bize yardımcı olmaktadır. Sonuç olarak, lösemi kök hücreleri üzerinde yapılan çalışmalar insanoğluna yakın gelecekte löseminin üstesinden gelebilmesi için bir fırsat sunmaktadır.

Anahtar sözcükler: Kök hücre, lösemi kök hücresi, hücre farklılaşma, akut miyeloid lösemi, kronik myelositer lösemi

Abstract

Cancer as an important group of disease is characterized by the abnormal differentiation and proliferation of the cells without normal control. Cancer is generally originated from only a cell named cancer stem cell. Because of the selfrenewal capacity of cancer stem cells, over proliferation of tumor cells occurs. Despite of the importance of cancer stem cells in tumorogenesis, the existence in a tumor tissue is very few. The knowledge of cancer stem cell biology is most advanced in leukemias. Leukemia is a group of malignant diseases of the blood system, originated from hematopoietic cancer stem cells and characterized by uncontrolled overproduction of leukocytes. The molecular findings observed in cancer stem cells in various types of leukemias and normal hemaopoietic stem cells differentiation represented the difference between normal and pathologic cell differentiation. Cell surface markers defined in different maturation steps in leukemias had been used for the identification of the pure stem cells in the same stage. These findings had been used for the understanding the transformation and differentiation of leukemia stem cells. Also, xenotransplantation studies give us the mouse models which have different type of leukemia by using the pure leukemia stem cells. The new molecular markers observed in these further mouse experiments can give the opportunity to be used in the diagnosis and prognosis of leukemia patients. Understanding the biology of leukemia stem cells may help us in the development of new targeted chemotherapy strategies in cancer cases. So, the further experiments on leukemia stem cells seems having a chance for mankind to overcome the leukemia problem in near future.

Keywords: Stem cell, leukemia stem cell, cell differantiation, acute myeloid leukemia, chronic myeloid leukemia

Anahtar Kelimeler

Kaynakça

Evans M. Discovering pluripotency: 30 years of mouse embryonic stem cells. Nat Rev Mol Cell Biol 2011; 12: 680-6.
Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood 1993; 81: 2844-53.
Banerjee P, Crawford L, Samuelson E, Feuer G. Hematopoietic stem cells and retroviral infection. Retrovirology 2010; 7: 8.
Krause DS. Plasticity of marrow-derived stem cells. Gene Ther 2002; 9: 754-8.
Kondo M, Wagers AJ, Manz MG, Prohaska SS, Scherer DC, Beilhack GF, Shizuru JA, Weissman IL. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu Rev Immunol 2003; 21: 759-806.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105-11.
Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th ed. New York: Garland Science; 2002: 23.
Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 2003; 3: 895-902.
Passegué E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc Natl Acad Sci U S A 2003; 100 Suppl 1: 11842-9.
Antonchuk J, Sauvageau G, Humphries RK. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 2002; 109: 39-45.
Thorsteinsdottir U, Mamo A, Kroon E, Jerome L, Bijl J, Lawrence HJ, Humphries K, Sauvageau G. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Blood 2002; 99: 121-9.
Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001; 2: 172-80.
Varnum-Finney B, Xu L, Brashem-Stein C, Nourigat C, Flowers D, Bakkour S, Pear WS, Bernstein ID. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 2000; 6: 127881.
Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 2003; 423: 409-14.
Krause DS, Van Etten RA. Right on target: eradicating leukemic stem cells. Trends Mol Med 2007; 13: 470-81.
Alison MR, Islam S, Lim SM. Number crunching in the cancer stem cell market. Breast Cancer Res 2009; 11: 302.
Warner JK, Wang JC, Hope KJ, Jin L, Dick JE. Concepts of human leukemic development. Oncogene 2004; 23: 7164-77.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-7.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645-8.
Castor A, Nilsson L, Astrand-Grundström I, Buitenhuis M, Ramirez C, Anderson K, Strömbeck B, Garwicz S, Békássy AN, Schmiegelow K, Lausen B, Hokland P, Lehmann S, Juliusson G, Johansson B, Jacobsen SE. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005; 11: 630-7.
Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y, Smith BD, Civin CI, Jones RJ. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332-6.
Manz MG, Miyamoto T, Akashi K, Weissman IL. Prospective isolation of human clonogenic common myeloid progenitors. Proc Natl Acad Sci USA 2002; 99: 11872-7.
Jordan CT, Upchurch D, Szilvassy SJ, Guzman ML, Howard DS, Pettigrew AL, Meyerrose T, Rossi R, Grimes B, Rizzieri DA, Luger SM, Phillips GL. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 2000; 14: 1777-84.
Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity 1994; 1: 66173.
van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, Stigter-van Walsum M, Zweegman S, Ossenkoppele GJ, Jan Schuurhuis G. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 2007; 110: 2659-66.
Wang JC, Lapidot T, Cashman JD, Doedens M, Addy L, Sutherland DR, Nayar R, Laraya P, Minden M, Keating A, Eaves AC, Eaves CJ, Dick JE. High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase. Blood 1998; 91: 2406-14.
Eisterer W, Jiang X, Christ O, Glimm H, Lee KH, Pang E, Lambie K, Shaw G, Holyoake TL, Petzer AL, Auewarakul C, Barnett MJ, Eaves CJ, Eaves AC. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia 2005; 19: 435-41.
Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med 2006; 12: 1175-80.
Hu Y, Swerdlow S, Duffy TM, Weinmann R, Lee FY, Li S. Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. Proc Natl Acad Sci USA 2006; 103: 16870-5.
Neering SJ, Bushnell T, Sozer S, Ashton J, Rossi RM, Wang PY, Bell DR, Heinrich D, Bottaro A, Jordan CT. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 2007; 110: 2578-85.
Dash AB, Williams IR, Kutok JL, Tomasson MH, Anastasiadou E, Lindahl K, Li S, Van Etten RA, Borrow J, Housman D, Druker B, Gilliland DG. A murine model of CML blast crisis induced by cooperation between BCR/ABL and NUP98/HOXA9. Proc Natl Acad Sci USA 2002; 99: 7622-7.
Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. Granulocytemacrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004; 351: 657-67.
Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, Luongo JL, Danet-Desnoyers GA, Bonnet D. Hematopoietic stem cells express multiple myeloid markers: implications for the origin and targeted therapy of acute myeloid leukemia. Blood 2005; 106: 4086-92.
Ebben JD, Zorniak M, Clark PA, Kuo JS. Introduction to induced pluripotent stem cells: advancing the potential for personalized medicine. World Neurosurg 2011; 76: 270-5.