Uloga adhezijskih molekula i izvanstanične potke u mijelodisplastičnom sindromu [Role of Adhesion Molecules and Extracellular Matrix in the Myelodysplastic Syndromes]

Ljubić, Nives (2010) Uloga adhezijskih molekula i izvanstanične potke u mijelodisplastičnom sindromu [Role of Adhesion Molecules and Extracellular Matrix in the Myelodysplastic Syndromes]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Aim of the study was to clarify interactions between hematopoietic cells and extracellular matrix in patients with MDS. It was analysed immunoexpression of certain proteins (CD31, CD44, laminin, fibronectin and APC- Adenomatous Poliposis Colli ), as well as cytogenetic fluorecence in situ hibridysation (FISH) analysis of 5q31-33 deletion. Also it was analyzed morphological characteristics of bone marrow (number and localization of blasts, mastocytes, osteoblasts, osteoclasts, osteoid, fybrosis) and certain biochemical and hematological indicators in serum and peripheral blood. According WHO and FAB criteria group of 50 patinets with MDS was divided in three subgroups. According FAB classification in first group were patients with low risk for transformation to AML, patients with RA and RARS. Second group consisted of patients with high risk for transformation to AML, patients with RAEB and RAEB-t. In third group were patients with CMML. According WHO classification in first group were patients with RA, RCMD and RARS. Second group of MDS patients consisted of patients with RAEB-1, RAEB-2 and AML, and in third group were patients with MDS/MPD. The highest CD44 immunoexpression was seen in second group of MDS. Higher CD44 immunoexpression in second MDS group with agressive clinical course of disease point to that higher adhesion of hematopoietic BM (bone marrow) cells to BM environment, which is probably connected to higher proliferation and/or deley of differentiation of BM hematopoetic cells. CD31 (PECAM) and fibronektin immunoexpression was not significantly different between all three groups of patients with MDS. The highest number of laminin positive blood vessels was observed in first and third groups of patients with MDS. For the first time seen morphological phenomenon of blood vessels branching mostly observed in RAEB and CMML could be also linked to angiogenesis that is connected to higher clonal proliferation of hematopoietic cells in these MDS types. According literature search, APC molecule was analyzed for the first time in MDS patients, and was negative in BM hematopoietic cells. There was no difference between all three groups of MDS patients for FISH analysis of l5q31-33- locus near APC gene. There was no statistical difference for atypical localization of immature percursors (ALIP), number of mastocytes, osteoblasts, osteoklasts, osteoid and fibrosis for all three groups of MDS patients. Levels of total serum proteins were significantly higher in second and third groups of MDS patients in comparison to the first group of patient. LDH was higher with bordeline statistical significance in second and third group of patients in comparison to first group of MDS patients.

Abstract in Croatian

Cilj rada bilo je istraživanje međusobne povezanosti hematopoetskih stanica i izvanstanične potke, odnosno mikrookoliša kod MDS-a. Analiziran je imunohistokemijski izražaj proteina (CD44, CD31, laminin, fibronektin i APC – Adenomatosis Polyposis Colli), molekularno-citogenetska FISH analiza delecije 5q31-33, zatim morfološki pokazatelji u koštanoj srži (broj i lokalizacija blasta, mastociti, osteoblasti, osteoklasti, osteoid, fibroza) te ukupni proteini i LDH u serumu i pokazatelji kompletne krvne slike. U skupini ispitanika bilo je 50 bolesnika s MDS-om koji su prema FAB-ovim i SZO-ovim kriterijima svrstani u tri skupine. Prema podjeli u skupine po FAB-ovoj klasifikaciji u prvoj skupini bili su bolesnici s niskim rizikom prelaska u akutnu mijeloičnu leukemiju (AML): bolesnici s RA-om i RARS-om, drugu su skupinu sačinjavali bolesnici s visokim rizikom prelaska u AML, bolesnici s RAEB-om i RAEB-t, a u trećoj skupini bili su bolesnici s CMML-om. Prema kriterijima SZO-a u prvoj su skupini bili bolesnici s RA-om, RCMD-om i RARS-om, u drugoj skupinu oni s RAEB-1, RAEB-2 i AML-om, dok su u trećoj skupini bili bolesnici s MDS-om/MPS-om. Uspoređujući tri skupine bolesnika s MDS-om nađen je najjači izražaj CD44 u drugoj skupini bolesnika s klinički agresivnijim oblikom bolesti, što bi moglo upućivati da je pojačana adhezija hematopoetskih stanica za mikrookoliš u koštanoj srži povezana s pojačanom proliferacijom nezrelih hematopoetskih stanica i/ili odgodom sazrijevanja hematopoetskih stanica. Nađen je granično veći broj laminin pozitivnih žila u pojedinim skupinama bolesnika s MDS-om, a opažen morfološki fenomen grananja laminin pozitivnih žila, koji je najprisutniji bio u RAEB-u i CMML-u, također bi mogao upućivati na angiogenezu povezanu s klonalnom proliferacijom hematopoetskih stanica. Izražaj CD31 (PECAM) i fibronektina nije bio značajno različit među svim trima skupinama bolesnika. Analizom APC, učinjenom po prvi put u hematopoetskim stanicama u bolesnika s MDS-om, nije nađen imunohistokemijski izražaj toga proteina. FISH analizom istraživala se delecija regije 5q31-33, gdje se nalazi gen za APC, i nije nađena razlika u pojavi ove citogenetske promjene između triju skupina bolesnika s MDS-om. Nalazi ALIP-a, broj mastocita, broj osteoblasta i osteoklasta, osteoid i fibroza nisu se značajno razlikovali među svim trima skupinama bolesnika. Razina ukupnih proteina u serumu bila je značajno viša u drugoj i trećoj skupini bolesnika u odnosu na prvu skupinu bolesnika, a vrijednosti LDH bile su na granici značajnosti, veće u drugoj i trećoj skupini bolesnika u odnosu na prvu skupinu bolesnika.

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