Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).

• Klíčová slova
• Drug therapy, Hematology, Leukemias, Oncology, Signal transduction,
• MeSH
• adenin * analogy a deriváty   farmakologie   MeSH
• chronická lymfatická leukemie * farmakoterapie   metabolismus   genetika   patologie   MeSH
• forkhead box protein O1 * metabolismus   genetika   MeSH
• fosforylace MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny metabolismus   genetika   MeSH
• piperidiny * farmakologie   MeSH
• protein RICTOR * genetika   metabolismus   MeSH
• proteinkinasa BTK metabolismus   genetika   antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-akt * metabolismus   genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyrimidiny * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenin * MeSH
• BTK protein, human MeSH Prohlížeč
• forkhead box protein O1 * MeSH
• FOXO1 protein, human MeSH Prohlížeč
• ibrutinib MeSH Prohlížeč
• nádorové proteiny MeSH
• piperidiny * MeSH
• protein RICTOR * MeSH
• proteinkinasa BTK MeSH
• protoonkogenní proteiny c-akt * MeSH
• pyrazoly * MeSH
• pyrimidiny * MeSH

Several in vitro models have been developed to mimic chronic lymphocytic leukemia (CLL) proliferation in immune niches; however, they typically do not induce robust proliferation. We prepared a novel model based on mimicking T-cell signals in vitro and in patient-derived xenografts (PDXs). Six supportive cell lines were prepared by engineering HS5 stromal cells with stable expression of human CD40L, IL4, IL21, and their combinations. Co-culture with HS5 expressing CD40L and IL4 in combination led to mild CLL cell proliferation (median 7% at day 7), while the HS5 expressing CD40L, IL4, and IL21 led to unprecedented proliferation rate (median 44%). The co-cultures mimicked the gene expression fingerprint of lymph node CLL cells (MYC, NFκB, and E2F signatures) and revealed novel vulnerabilities in CLL-T-cell-induced proliferation. Drug testing in co-cultures revealed for the first time that pan-RAF inhibitors fully block CLL proliferation. The co-culture model can be downscaled to five microliter volume for large drug screening purposes or upscaled to CLL PDXs by HS5-CD40L-IL4 ± IL21 co-transplantation. Co-transplanting NSG mice with purified CLL cells and HS5-CD40L-IL4 or HS5-CD40L-IL4-IL21 cells on collagen-based scaffold led to 47% or 82% engraftment efficacy, respectively, with ~20% of PDXs being clonally related to CLL, potentially overcoming the need to co-transplant autologous T-cells in PDXs.

• MeSH
• buňky stromatu * metabolismus   patologie   MeSH
• chronická lymfatická leukemie * patologie   genetika   farmakoterapie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• interleukin-21 MeSH
• interleukiny genetika   metabolismus   MeSH
• kokultivační techniky * MeSH
• lidé MeSH
• ligand CD40 * metabolismus   genetika   MeSH
• myši MeSH
• proliferace buněk * MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• interleukin-21 MeSH
• interleukiny MeSH
• ligand CD40 * MeSH

• MeSH
• antigeny CD20 metabolismus   MeSH
• chinazolinony farmakologie   terapeutické užití   MeSH
• chronická lymfatická leukemie * farmakoterapie   MeSH
• interleukin-4 MeSH
• lidé MeSH
• protinádorové látky * terapeutické užití   MeSH
• puriny farmakologie   terapeutické užití   MeSH
• transkripční faktor STAT6 MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD20 MeSH
• chinazolinony MeSH
• idelalisib MeSH Prohlížeč
• interleukin-4 MeSH
• protinádorové látky * MeSH
• puriny MeSH
• STAT6 protein, human MeSH Prohlížeč
• transkripční faktor STAT6 MeSH

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in the peripheral blood and the decision to return to immune niches. Our study provided evidence that CXCR4/CD5 intraclonal subpopulations can be used to study the regulation of migration of CLL cells. We performed RNA profiling of CXCR4dimCD5bright vs CXCR4brightCD5dim CLL cells and identified differential expression of dozens of molecules with a putative function in cell migration. GRB2-associated binding protein 1 (GAB1) positively regulated CLL cell homing capacity of CXCR4brightCD5dim cells. Gradual GAB1 accumulation in CLL cells outside immune niches was mediated by FoxO1-induced transcriptional GAB1 activation. Upregulation of GAB1 also played an important role in maintaining basal phosphatidylinositol 3-kinase (PI3K) activity and the "tonic" AKT phosphorylation required to sustain the survival of resting CLL B cells. This finding is important during ibrutinib therapy, because CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors, alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

• MeSH
• adaptorové proteiny signální transdukční biosyntéza   MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• chronická lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• forkhead box protein O1 metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• piperidiny farmakologie   MeSH
• pohyb buněk * MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• regulace genové exprese u leukemie * MeSH
• signální transdukce * MeSH
• upregulace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• adenin MeSH
• forkhead box protein O1 MeSH
• FOXO1 protein, human MeSH Prohlížeč
• GAB1 protein, human MeSH Prohlížeč
• ibrutinib MeSH Prohlížeč
• piperidiny MeSH
• protoonkogenní proteiny c-akt MeSH

B-cell receptor (BCR) signaling and T-cell interactions play a pivotal role in chronic lymphocytic leukemia (CLL) pathogenesis and disease aggressiveness. CLL cells can use microRNAs (miRNAs) and their targets to modulate microenvironmental interactions in the lymph node niches. To identify miRNA expression changes in the CLL microenvironment, we performed complex profiling of short noncoding RNAs in this context by comparing CXCR4/CD5 intraclonal cell subpopulations (CXCR4dimCD5bright vs CXCR4brightCD5dim cells). This identified dozens of differentially expressed miRNAs, including several that have previously been shown to modulate BCR signaling (miR-155, miR-150, and miR-22) but also other candidates for a role in microenvironmental interactions. Notably, all 3 miR-29 family members (miR-29a, miR-29b, miR-29c) were consistently down-modulated in the immune niches, and lower miR-29(a/b/c) levels associated with an increased relative responsiveness of CLL cells to BCR ligation and significantly shorter overall survival of CLL patients. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a novel direct target of miR-29s and revealed that higher TRAF4 levels increase CLL responsiveness to CD40 activation and downstream nuclear factor-κB (NF-κB) signaling. In CLL, BCR represses miR-29 expression via MYC, allowing for concurrent TRAF4 upregulation and stronger CD40-NF-κB signaling. This regulatory loop is disrupted by BCR inhibitors (bruton tyrosine kinase [BTK] inhibitor ibrutinib or phosphatidylinositol 3-kinase [PI3K] inhibitor idelalisib). In summary, we showed for the first time that a miRNA-dependent mechanism acts to activate CD40 signaling/T-cell interactions in a CLL microenvironment and described a novel miR-29-TRAF4-CD40 signaling axis modulated by BCR activity.

• MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• antigeny CD40 genetika   metabolismus   MeSH
• chronická lymfatická leukemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• dospělí MeSH
• faktor 4 asociovaný s receptory TNF genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádorové buňky kultivované MeSH
• následné studie MeSH
• piperidiny farmakologie   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-bcr antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-myc genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• antigeny CD40 MeSH
• BCR protein, human MeSH Prohlížeč
• faktor 4 asociovaný s receptory TNF MeSH
• ibrutinib MeSH Prohlížeč
• mikro RNA MeSH
• MIRN29a microRNA, human MeSH Prohlížeč
• MYC protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• piperidiny MeSH
• protoonkogenní proteiny c-bcr MeSH
• protoonkogenní proteiny c-myc MeSH
• TRAF4 protein, human MeSH Prohlížeč

Introduction of small-molecule inhibitors of B-cell receptor signaling and BCL2 protein significantly improves therapeutic options in chronic lymphocytic leukemia. However, some patients suffer from adverse effects mandating treatment discontinuation, and cases with TP53 defects more frequently experience early progression of the disease. Development of alternative therapeutic approaches is, therefore, of critical importance. Here we report details of the anti-chronic lymphocytic leukemia single-agent activity of MU380, our recently identified potent, selective, and metabolically robust inhibitor of checkpoint kinase 1. We also describe a newly developed enantioselective synthesis of MU380, which allows preparation of gram quantities of the substance. Checkpoint kinase 1 is a master regulator of replication operating primarily in intra-S and G2/M cell cycle checkpoints. Initially tested in leukemia and lymphoma cell lines, MU380 significantly potentiated efficacy of gemcitabine, a clinically used inducer of replication stress. Moreover, MU380 manifested substantial single-agent activity in both TP53-wild type and TP53-mutated leukemia and lymphoma cell lines. In chronic lymphocytic leukemia-derived cell lines MEC-1, MEC-2 (both TP53-mut), and OSU-CLL (TP53-wt) the inhibitor impaired cell cycle progression and induced apoptosis. In primary clinical samples, MU380 used as a single-agent noticeably reduced the viability of unstimulated chronic lymphocytic leukemia cells as well as those induced to proliferate by anti-CD40/IL-4 stimuli. In both cases, effects were comparable in samples harboring p53 pathway dysfunction (TP53 mutations or ATM mutations) and TP53-wt/ATM-wt cells. Lastly, MU380 also exhibited significant in vivo activity in a xenotransplant mouse model (immunodeficient strain NOD-scid IL2Rγnull ) where it efficiently suppressed growth of subcutaneous tumors generated from MEC-1 cells.

• MeSH
• apoptóza MeSH
• buněčný cyklus MeSH
• checkpoint kinasa 1 antagonisté a inhibitory   MeSH
• chemorezistence účinky léků   MeSH
• chronická lymfatická leukemie farmakoterapie   genetika   patologie   MeSH
• deoxycytidin analogy a deriváty   farmakologie   MeSH
• gemcitabin MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• mutace * MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádorové biomarkery genetika   MeSH
• nádorové buňky kultivované MeSH
• nádorový supresorový protein p53 genetika   MeSH
• piperidiny farmakologie   MeSH
• proliferace buněk MeSH
• protinádorové antimetabolity farmakologie   MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• synergismus léků * MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• checkpoint kinasa 1 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• deoxycytidin MeSH
• gemcitabin MeSH
• inhibitory proteinkinas MeSH
• MK-8776 MeSH Prohlížeč
• MU380 MeSH Prohlížeč
• nádorové biomarkery MeSH
• nádorový supresorový protein p53 MeSH
• piperidiny MeSH
• protinádorové antimetabolity MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• TP53 protein, human MeSH Prohlížeč

The variable clinical course in chronic lymphocytic leukaemia (CLL) largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We show that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling regulator and its high levels are associated with worse CLL prognosis. We identified microRNA (miRNA) miR-34a as the most prominently upregulated miRNA during DDR in CLL cells in vitro and in vivo during FCR therapy (fludarabine, cyclophosphamide, rituximab). MiR-34a induced by DDR activation and p53 stabilization potently represses FOXP1 expression by binding in its 3'-UTR. The low FOXP1 levels limit BCR signalling partially via derepressing BCR-inhibitory molecule CD22. We also show that low miR-34a levels can be used as a biomarker for worse response or shorter progression free survival in CLL patients treated with FCR chemoimmunotherapy, and shorter overall survival, irrespective of TP53 status. Additionally, we have developed a method for the absolute quantification of miR-34a copies and defined precise prognostic/predictive cutoffs. Overall, herein, we reveal for the first time that B cells limit their BCR signalling during DDR by down-modulating FOXP1 via DDR-p53/miR-34a axis.

• MeSH
• chronická lymfatická leukemie farmakoterapie   genetika   metabolismus   patologie   MeSH
• cyklofosfamid aplikace a dávkování   MeSH
• dospělí MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• míra přežití MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• následné studie MeSH
• poškození DNA účinky léků   genetika   MeSH
• prognóza MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• receptory antigenů B-buněk genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• represorové proteiny genetika   metabolismus   MeSH
• rituximab aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• signální transdukce MeSH
• vidarabin aplikace a dávkování   analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cyklofosfamid MeSH
• fludarabine MeSH Prohlížeč
• forkhead transkripční faktory MeSH
• FOXP1 protein, human MeSH Prohlížeč
• mikro RNA MeSH
• MIRN34 microRNA, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• receptory antigenů B-buněk MeSH
• represorové proteiny MeSH
• rituximab MeSH
• vidarabin MeSH

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

• MeSH
• aktivace transkripce MeSH
• difúzní velkobuněčný B-lymfom genetika   patologie   MeSH
• down regulace MeSH
• folikulární lymfom diagnóza   genetika   patologie   MeSH
• forkhead transkripční faktory genetika   MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• nádorová transformace buněk genetika   patologie   MeSH
• prognóza MeSH
• protoonkogenní proteiny c-myc genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• represorové proteiny genetika   MeSH
• upregulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• forkhead transkripční faktory MeSH
• FOXP1 protein, human MeSH Prohlížeč
• mikro RNA MeSH
• MIRN150 microRNA, human MeSH Prohlížeč
• protoonkogenní proteiny c-myc MeSH
• represorové proteiny MeSH

• MeSH
• antigeny CD20 metabolismus   MeSH
• biologické markery MeSH
• buněčná cytotoxicita závislá na protilátkách imunologie   MeSH
• chronická lymfatická leukemie farmakoterapie   imunologie   metabolismus   patologie   MeSH
• cytotoxicita imunologická MeSH
• fenotyp MeSH
• komplement imunologie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí účinky léků   imunologie   MeSH
• protinádorové látky imunologicky aktivní farmakologie   terapeutické užití   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD20 MeSH
• biologické markery MeSH
• komplement MeSH
• protinádorové látky imunologicky aktivní MeSH
• receptory antigenů B-buněk MeSH
• rituximab MeSH

Agents targeting B-cell receptor (BCR) signaling-associated kinases such as Bruton tyrosine kinase (BTK) or phosphatidylinositol 3-kinase can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab, obinutuzumab, or ofatumumab) for treatment of B-cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) upregulate CD20 on CLL cells and that administering ibrutinib downmodulates CD20 (MS4A1) expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4(dim)CD5(bright) subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4(bright)CD5(dim) cells). We found that CD20 is directly upregulated by CXCR4 ligand stromal cell-derived factor 1 (SDF-1α, CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1α-mediated CD20 upregulation. Ibrutinib also downmodulated Mcl1 levels in CLL cells in vivo and in coculture with stromal cells. Overall, our study provides a first detailed mechanistic explanation of CD20 expression regulation in the context of chemokine signaling and microenvironmental interactions, which may have important implications for microenvironment-targeting therapies.

• MeSH
• adenin analogy a deriváty   MeSH
• antigeny CD20 chemie   genetika   metabolismus   MeSH
• chemokin CXCL12 genetika   metabolismus   MeSH
• chronická lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• piperidiny MeSH
• pyrazoly farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• receptory CXCR4 genetika   metabolismus   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce MeSH
• upregulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenin MeSH
• antigeny CD20 MeSH
• chemokin CXCL12 MeSH
• CXCL12 protein, human MeSH Prohlížeč
• CXCR4 protein, human MeSH Prohlížeč
• ibrutinib MeSH Prohlížeč
• piperidiny MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• receptory CXCR4 MeSH