Spontaneous Granulocytic Leukemia hauv A NOD/Shi-scid IL-2R null Mouse

Abstract:Ntawm no, peb tshaj tawm ib rooj plaub ntawm tus kheej granulocytic leukemia nyob rau hauv ib tug 51-cov txiv neej hnub nyoog ib asthiv NOD/Shi-scidIL-2R null (NOG) nas. Nas pomProgressive anemiathiabua pa nyuaj. Macroscopically, tus po yog discolored thiab loj. Histologically, cov pob txha pob txha ntawm lubsternumthiab femur yog heev cellular thiab yuav luag tag nrho covneoplastic hlwb. Lub nuclei ntawm neoplastic hlwb loj, oval mus rau me ntsis tsis xwm yeem nyob rau hauv cov duab, thiab ib tug me me ntawm cov hlwb muaj.raum- los yog lub nplhaib-shaped nuclei.Neoplastic hlwbFeem ntau infiltrated lub cev, thiab tus po thiab daim siab tau prominently koom tes. Immunohistochemically, cov neeg coob ntawm cov hlwb neoplastic hauv cov pob liab liab ntawm tus po thiab sinusoid ntawm daim siab tau zoo raumyeloperoxidase. Raws li cov yam ntxwv histological, rooj plaub no tau kuaj pomgranulocytic leukemia. Cov ntaub ntawv tshiab no ntawmspontaneous qogtej zaum yuav muaj txiaj ntsig zoo rau kev siv cov nas no hauv kev tshawb fawb ntxiv. (DOI: 10.1293/tox.2020-0092; J Toxicol Pathol 2021; 34: 241–244)

Ntsiab lus: granulocytic leukemia, NOG nas, spontaneous tumor

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Spontaneous granulocytic leukemiatsis tshua muaj tshwm sim nyob rau hauv ntau hom nas, txawm hais tias cov tshuaj tua kab mob thiab cov hluav taws xob ionizing tuaj yeem ua rau muaj qhov tshwm sim hauv qee cov nas 1, 2. NOD/Shi-scid IL-2R null (NOG) nas mob hnyav heev.tsiaj tiv thaiv kab mob, thiab tam sim no tsis xws luag nyob rau hauv T-, B-, thiab ntuj killer hlwb, thiab ua hauj lwm tsis zoo macrophages thiab dendritic hlwb los ntawm knockout ntawm IL-2 receptor-chain (IL2R c) rau hauv NOD-scid strain3. Cov nas no yog siv rau cov kev sim uas tsis yog chaw kho mob, xws li kev kuaj mob qog noj ntshav, txhawm rau ntsuas qhov zoo thiab kev nyab xeeb ntawm cov khoom siv roj ntsha rau cov tshuaj regenerative siv tib neeg los ntawm cov cell / cov ntaub so ntswg, vim tias qhov ua tau zoo ntawm xenogeneic cells4-6. Txawm hais tias lub xeev tiv thaiv kab mob thiab nws qhov cuam tshuam rau xenografts tau kawm zoo, cov ntaub ntawv me me muaj nyob ntawm cov qog nqaij hlav tshwm sim hauv cov nas no, xws li thymic lymphoma,mammaryqog adenoma / adenocarcinoma, bronchioloalveolar carcinoma, mob rhabdomyosarcoma, thiab teratoma 7. Ntawm no, peb tshaj tawm ib kis ntawm granulocytic leukemia nyob rau hauv ib tug 51-lub lim tiam-laus txiv neej NOG nas.

Tus tsiaj no tau txais los ntawm In-Vivo Science Inc. (Kanagawa, Nyiv) thaum muaj hnub nyoog 6 lub lis piam thiab raug khaws cia tsis kho. Tus tsiaj tau muab tso rau hauv ib lub tawb yas nrog ib tus kheej ventilated tawb system (Maxi Miser Caging System; Oriental Giken Inc., Tokyo, Nyiv) nyob rau hauv ib puag ncig tswj kev tiv thaiv chav tsev, uas tau khaws cia ntawm qhov kub ntawm 22 ± 2 degree nrog cov av noo ntawm 50 ± 20% thiab 12-h lub teeb / tsaus voj voog. Tus nas tau noj cov khoom noj autoclaved pelleted (CRF-1; Charles River Nyiv, Inc., Tokyo, Nyiv) nrog autoclaved kais dej thiab libitum. Cov tsiaj no tau ua raws li cov txheej txheem pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab Siv Khoom ntawm CMIC Pharma Science Co., Ltd., uas tau lees paub los ntawm AAALAC International.

Tus nas no tau pom cov tsos mob ntawm kev qaug zog, xws li ntshav liab, ua pa nyuaj, thiab lub cev hnyav ntawm 49 thiab 51 lub lis piam. Tus tsiaj tau euthanized thaum muaj hnub nyoog 51 lub lis piam. Thaum necropsy, tus po tau tawg thiab loj. Tsis muaj qhov pom tseeb txawv txav tag nrho tau pom nyob rau hauv lwm lub cev. Cov thymus thiab lymph node yog atrophic, zoo ib yam li cov nas NOG ib txwm.

Tag nrho cov khoom nruab nrog cev thiab cov ntaub so ntswg kuaj tau niaj hnub sau, kho nyob rau hauv 10% nruab nrab buffered formalin, embedded nyob rau hauv paraffin, thiab sectioned ntawm kwv yees li 3 μm. Rau nws mus rau kev kuaj mob pathological, ntu tau stained nrog hematoxylin thiab eosin (HE). Cov seem ntawm tus po thiab daim siab yog cov tshuaj immunohistochemically stained rau luav los tiv thaiv tib neeg myeloperoxidase (MPO) polyclonal antibody (Dako Nyiv, Tokyo, Nyiv) raws li ib tug myeloid cell marker, luav anti-tib neeg CD3 monoclonal antibody (Nichirei Biosciences Inc., Tokyo, Nyiv. ) raws li T cell marker, thiab luav tiv thaiv tib neeg Pax-5 monoclonal antibody (Abcam Inc., Cambridge, UK) raws li B cell marker8. Cov seem tau muab tso rau hauv cov tshuaj tiv thaiv hauv chav sov li 1 h, thiab kev tiv thaiv kab mob tau ua los ntawm Histofine® MOUSESTAIN KIT (Nichirei Biosciences Inc.) nrog 3,3′-diaminobenzidine/H2O2 ua cov chromogen. Immunostained seem yog cescounterstained nrog hematoxylin.

Histopathologically, cov pob txha pob txha ntawm lub sternum thiab femur yog heev cellular thiab yuav luag tag nrho cov neoplastic hlwb (Fig. 1A). Cov nqaij rog raug tshem tawm tag nrho. Muaj qee lub sijhawm cellular foci uas muaj erythroid thiab megakaryocytic cov ntsiab lus hauv cov pob txha, uas tau suav tias yog cov seem ntawmnormal hematopoiesis. Feem ntau cov neoplastic hlwb pom ib tug blastic zoo li, tus yam ntxwv los ntawm loj, oval mus rau me ntsis irregularly zoo li tus nuclei, thiab nrog ib tug reticular chromatin muaj ib los yog ntau tshaj nucleoli. Muaj qee lub hlwb uas muaj lub raum- lossis lub nplhaib-zoo li tus nuclei thiab ob peb lub hlwb uas muaj lobed nuclei kuj muaj (Fig. 1B). Granules nyob rau hauv cytoplasm ntawm neoplastic hlwb tsis pom tseeb nyob rau hauv cov seem stained nrog HE. Ntau cov duab mitotic tau pom nyob rau hauv cov pob txha, thiab qee zaus lub cev apoptotic kuj tau pom. Cov hlwb neoplastic markedly invaded lub periosteum thiab cov leeg pob txha nyob ib puag ncig. Muaj ntau infiltration ntawm neoplastic hlwb mus rau lwm yam kabmob thiab cov ntaub so ntswg, thiab tus po thiab daim siab tau prominently koom tes. Nyob rau hauv tus po, cov hlwb neoplastic tau pom thoob plaws hauv cov tawv nqaij liab (Fig. 2). Capsular infiltration ntawm neoplastic hlwb tau tshwm sim. Qee qhov kev txhim kho erythroid series thiab megakaryocytes tau pom. Megakaryocytes muaj ib lossis qee cov hlwb myeloid hauv cytoplasm, qhia txog emperipolesis, qee zaus pom. Hauv daim siab, cov hlwb neoplastic infiltrated Glisson's capsule thiab hepatic sinusoids diffusely (Fig. 3). Neoplastic hlwb nrog raum- lossis lub nplhaib-zoo li tus nuclei kuj tau tshwm sim hauv qee cov hlab ntsha. Qee cov hepatocytes hauv thaj chaw periportal, nrog cov neoplastic cell infiltration tseem ceeb, pom tias degeneration los yog necrosis, thaum lub cev qauv ntawm lub siab lobule tseem nyob twj ywm. Neoplastic cell infiltration kuj pom muaj nyob rau hauv lwm yam kabmob, nrog rau cov phab ntsa alveolar thiab perivascular cheeb tsam ntawm lub ntsws, interstadium nyob rau hauv lub raum, sinusoid nyob rau hauv lub qog adrenal, thiab mucosa thiab submucosa nyob rau hauv lub plab ( plab thiab hnyuv). Immunohistochemically, cov neeg coob ntawm cov hlwb neoplastic nyob rau hauv cov pob liab liab ntawm tus po (Fig. 4) thiab cov sinusoid ntawm lub siab yog qhov zoo rau MPO. CD3 thiab Pax-5 cov hlwb zoo tsis tau kuaj pom. Cov txiaj ntsig ntawm CD3 thiab Pax-5 immunostaining zoo ib yam li cov poov xab ntawm cov nas NOG ib txwm, uas yog histologically hypoplastic thiab tsis pom CD3 lossis Pax{13}} cov hlwb zoo.

Kev tshawb nrhiav Immunohistochemical qhia tias cov hlwb neoplastic yog los ntawm cov kab mob myeloid. Hauv qee qhov chaw koom nrog, tshwj xeeb tshaj yog tus po thiab daim siab, qee lub hlwb muaj lub raum-, lub nplhaib-, lossis cov duab lobed qhia txog kev sib txawv ntawm cov kab mob myeloid. Cov kev tshawb pom no qhia tias cov hlwb neoplastic yog muab los ntawm cov granulocytes tsis paub qab hau. Cov ntaub ntawv ntawm myelopoiesis hnyav tuaj yeem tshwm sim los ntawm qhov muaj ntawm txhua hom kev txhim kho myeloid series, piv rau qhov tseem ceeb ntawm cov hlwb tsis paub qab hau hauv leukemia. Tsis tas li ntawd, kev mob ntshav siab zuj zus yog ib qho kev kuaj mob ntawm granulocytic leukemia, thiab nce hauv erythroid thiab megakaryocytic hlwb tsis zoo1. Cov neeg me ntawm granulocytes nrog lobed nuclei nyob rau hauv thaj chaw muaj kev cuam tshuam yam tsis muaj kev mob tshwm sim qhia tau tias qhov kev tshawb pom ntawm cov ntaub ntawv tam sim no yog neoplastic thiab tsis reactive myelopoiesis.

Hauv granulocytic leukemia, cov pob txha pob txha yuav raug hloov los ntawm cov hlwb tsis paub tab thiab paub tab. Hauv tsab ntawv tshaj tawm dhau los ntawm lwm hom nas, cov hlwb neoplastic no tau nkag mus rau hauv daim siab, tus po, lymph nodes, thiab lwm yam.2, thiab cov hlwb no nyob rau hauv tus po thiab daim siab feem ntau nyob hauv cov nqaij liab thiab ib ncig ntawm Glisson's capsule1. Yog li, leukemic cell faib nyob rau hauv cov ntaub ntawv tam sim no yog zoo ib yam li ntawd nyob rau hauv cov ntaub ntawv dhau los. Raws li morphology ntawm cov hlwb, granulocytic leukemia nyob rau hauv nas tau muab faib ua ob hom: hom menyuam yaus, uas yog piv rau tib neeg mob myelogenous leukemia, thiab hom mature rau tib neeg mob myelogenous leukemia1. Hauv cov menyuam yaus, cov hlwb neoplastic nyob rau hauv cov pob txha, spleen, thiab daim siab tau tswj hwm los ntawm cov hlwb tsis zoo, qhov uas cov ntsiab lus myeloid sawv cev rau ntau qib ntawm kev loj hlob tuaj yeem pom thiab feem pua ​​​​ntawm cov myeloblasts tsawg hauv qee qhov kev paub tab2, 9. Cov ntaub ntawv tam sim no, cov hlwb leukemic tau tswj hwm los ntawm daim ntawv tsis paub qab hau nrog loj, oval mus rau me ntsis irregularly zoo li tus nuclei. Hauv kev tshaj tawm, xav txog cov kev tshawb pom pom tias kev noj qab haus huv tsis zoo, suav nrog kev mob ntshav qab zib ntau zuj zus thiab ua pa ua pa nyuaj, txhim kho mob hnyav; yog li ntawd, cov ntaub ntawv tam sim no yog suav tias yog hom menyuam yaus.

Daim duab 1. Histological dluab ntawm cov pob txha pob txha ntawm femur. A: Neoplastic hlwb diffusely proliferate, yog li hloov cov pob txha pob txha. B: Lub nuclei loj, oval mus rau me ntsis tsis xwm yeem nyob rau hauv cov duab. Ib tug me me ntawm cov hlwb muaj lub raum- (daj xub taub hau), nplhaib- (ntsuab xub taub), los yog lobe- (dawb xub taub hau) zoo li tus nuclei. Daim duab mitotic yog qhia los ntawm lub xub dawb. Nws stains. Dub bar =50 μm (A), 10 μm (B).

Hauv kev tshaj tawm yav dhau los ntawm NOG nas, cov kab mob neoplastic feem ntau tsis tshua muaj; Txawm li cas los xij, thymic lymphoma tau tshaj tawm ntawm 0.82% hauv pawg hnub nyoog li ntawm 16 txog 40 lub lis piam 7, 10. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, spontaneous ous granulocytic leukemia tsis tau qhia yav dhau los hauv NOG nas. Hauv ntau hom nas, suav nrog B6C3F1 thiab BALB/c, granulocytic leukemia tsis tshua muaj tshwm sim 2, 11, thiab tsis tau tshaj tawm rau cov nas no thaum muaj hnub nyoog 12 hli lossis qis dua. Cov ntaub ntawv tam sim no tau tsim cov kab mob ntshav qab zib granulocytic thaum muaj hnub nyoog 51 lub lis piam, uas yog hnub nyoog hluas. Cov ntaub ntawv tshiab no ntawm cov qog nqaij hlav tuaj yeem pab tau rau kev siv cov nas no hauv kev tshawb fawb ntxiv.