The protein cereblon (CRBN) is a substrate receptor of the cullin 4-really interesting new gene (RING) E3 ubiquitin ligase complex CRL4CRBN. Targeting CRBN mediates selective protein ubiquitination and subsequent degradation via the proteasome. This review describes novel thalidomide analogs, immunomodulatory drugs, also known as CRBN E3 ubiquitin ligase modulators or molecular glues (avadomide, iberdomide, CC-885, CC-90009, BTX-1188, CC-92480, CC-99282, CFT7455, and CC-91633), and CRBN-based proteolysis targeting chimeras (PROTACs) with increased efficacy and potent activity for application in hematologic malignancies. Both types of CRBN-binding drugs, molecular glues, and PROTACs stimulate the interaction between CRBN and its neosubstrates, recruiting target disease-promoting proteins and the E3 ubiquitin ligase CRL4CRBN. Proteins that are traditionally difficult to target (transcription factors and oncoproteins) can be polyubiquitinated and degraded in this way. The competition of CRBN neosubstrates with endogenous CRBN-interacting proteins and the pharmacology and rational combination therapies of and mechanisms of resistance to CRL4CRBN modulators or CRBN-based PROTACs are described.

• MeSH
• hematologické nádory * farmakoterapie   MeSH
• lidé MeSH
• proteasy * chemie   genetika   metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• ubikvitinace MeSH
• ubikvitinligasy chemie   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Incorrectly expressed or mutated proteins associated with hematologic malignancies have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies. But the majority of these intracellular proteins are without active sites and antigens. PROTACs, proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes the ubiquitin-proteasome system for the degradation of specific proteins in the cell. In many cases, including hematologic malignancies, inducing protein degradation as a therapeutic strategy offers therapeutic benefits over classical enzyme inhibition connected with resistance to inhibitors. Limitations of small-molecule inhibitors are shown. PROTACs can polyubiquitinate and mark for degradation of "undruggable"proteins, e.g. transcription factor STAT3 and scaffold proteins. Today, this technology is used in preclinical studies in various hematologic malignancies, mainly for targeting drug-resistant bromodomain and extraterminal proteins and Bruton tyrosine kinase. Several mechanisms limiting selectivity and safety of PROTAC molecules function are also discussed.

• MeSH
• hematologické nádory farmakoterapie   metabolismus   MeSH
• leukemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• lymfom farmakoterapie   metabolismus   MeSH
• objevování léků * MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• proteolýza účinky léků   MeSH
• protinádorové látky chemie   farmakologie   MeSH
• ubikvitinace účinky léků   MeSH
• ubikvitinligasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Myelodysplastic syndromes (MDS) are preleukemic disorders characterized by clonal growth of mutant hematopoietic stem and progenitor cells. MDS are associated with proinflammatory signaling, dysregulated immune response, and cell death in the bone marrow (BM). Aging, autoinflammation and autoimmunity are crucial features of disease progression, concordant with promoting growth of malignant clones and accumulation of mutations. Suprabasin (SBSN), a recently proposed proto-oncogene of unknown function, physiologically expressed in stratified epithelia, is associated with poor prognosis of several human malignancies. Here, we showed that SBSN is expressed in the BM by myeloid cell subpopulations, including myeloid-derived suppressor cells, and is secreted into BM plasma and peripheral blood of MDS patients. The highest expression of SBSN was present in a patient group with poor prognosis. SBSN levels in the BM correlated positively with blast percentage and negatively with CCL2 chemokine levels and lymphocyte count. In vitro treatment of leukemic cells with interferon-gamma and demethylating agent 5-azacytidine (5-AC) induced SBSN expression. This indicated that aberrant cytokine levels in the BM and epigenetic landscape modifications in MDS patients may underlie ectopic expression of SBSN. Our findings suggest SBSN as a candidate biomarker of high-risk MDS with a possible role in disease progression and therapy resistance.

• MeSH
• azacytidin farmakologie   MeSH
• biologické markery krev   metabolismus   MeSH
• chemokin CCL2 metabolismus   MeSH
• diferenciační antigeny krev   genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• interferon gama farmakologie   MeSH
• kompartmentace buňky účinky léků   MeSH
• kostní dřeň metabolismus   MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• myelodysplastické syndromy krev   metabolismus   MeSH
• myeloidní buňky účinky léků   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny krev   genetika   metabolismus   MeSH
• počet lymfocytů MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Inhibice proteinů nízkomolekulárními inhibitory je omezena na enzymy a receptory, které tvoří přibližně 25 % lidského proteomu. Většina proteinů, jako jsou transkripční faktory, strukturální proteiny, regulační proteiny a proteiny bez funkce enzymu, je nedostupná (undruggable) pro inhibiční molekuly. Během posledních 20 let byl vyvinut postup založený na mechanismu indukované degradace proteinů, využívající polyubikvitinaci a rozklad v proteazomech pomocí PROTACs (proteolysis-targeting chimeras). Dvoufunkční molekuly PROTACs jsou složeny ze specifického ligandu pro protein určený k degradaci, spojky (linker) a ze specifického ligandu pro E3 ubikvitinligázu využívanou v polyubikvitinaci cílového proteinu pro jeho následnou degradaci v proteazomech. Uvedené dvoufunkční molekuly byly experimentálně úspěšně použity k degradaci řady proteinů, které hrají důležité funkce v patogenezi hematologických malignit a jsou předmětem tohoto souhrnného článku.

Inhibition of proteins with small-molecule inhibitors is restricted to receptors and enzymes which make up approximately 25% of the human proteome. The majority of proteins such as transcription factors, scaffolding proteins, regulatory proteins and non-enzymatic proteins are difficult (“undruggable“) targets for small-molecule inhibitors. In the past 20 years, new procedures have been developed based on the mechanism of inducible protein degradation that exploits polyubiquitination and degradation in proteasomes using proteolysis targeting chimeras (PROTACs). Bifunctional molecules (PROTACs) are composed of specific ligand for the protein of interest connected via a linker to a specific ligand for E3 ubiquitin ligase used in protein of interest polyubiquitination and its subsequent degradation in proteasomes. The presented bifunctional molecules have been successfully used experimentally in degradation of many proteins of interest that have important functions in the pathogenesis of haematological malignancies and are the subject of this review.

• Klíčová slova
• chimera pro cílenou proteolýzu (PROTAC), proteazom, E3 ubikvitinligáza,
• MeSH
• cílená molekulární terapie metody   MeSH
• inhibitory enzymů farmakologie   MeSH
• lékové transportní systémy * MeSH
• lidé MeSH
• objevování léků MeSH
• proteolýza * účinky léků   MeSH
• racionální návrh léčiv MeSH
• ubikvitin terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.

• MeSH
• imunomodulace účinky léků   MeSH
• lidé MeSH
• lymfom farmakoterapie   patologie   MeSH
• myelodysplastické syndromy farmakoterapie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid leukemia (AML) is likely associated with elimination of the residual disease by the immune system, and possible involvement of PD-L1 in this process remains to be elucidated. We analyzed PD-L1 expression on AML primary cells by flow cytometry and, in parallel, transcript levels were determined for the transcription variants v1 and v2. The ratio of v1/v2 cDNA correlated with the surface protein amount, and high v1/v2 levels were associated with worse overall survival (p = 0.0045). The prognostic impact of PD-L1 was limited to AML with mutated nucleophosmin and concomitant internal tandem duplications in the FLT3 gene (p less than 0.0001 for this particular AML subgroup).

• MeSH
• akutní myeloidní leukemie krev   genetika   MeSH
• antigeny CD274 krev   genetika   metabolismus   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• mutace MeSH
• nádorové biomarkery krev   genetika   metabolismus   MeSH
• tyrosinkinasa 3 podobná fms genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• hematologie MeSH
• myelodysplastické syndromy MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• hematologie a transfuzní lékařství
• NLK Publikační typ
• kolektivní monografie

Transformační růstový faktor beta (TGF-β) je cytokin pojmenovaný podle schopnosti transformovat normální fibroblasty v kultuře. Později bylo zjištěno, že TGF-β inhibuje růst epiteliálních a lymfoidních buněk. Rodina TGF-β zahrnuje TGF-β1, TGF-β2, TGF-β3, aktiviny A a B, nodal, myostatin, různé růstové diferenciační faktory (GDF), kostní morfogenetické proteiny (BMP) a anti-Müllerian hormon (AMH). Velký počet těchto ligand (více než třicet) se váže k daleko menšímu počtu specifických transmembránových receptorů na povrchu buněk a vnitrobuněčných signálních molekul. Aktivace receptorů pro TGF-β a jejich fosforylace je spojena s myelosupresí a neefektivní erytropoézou u myelodysplastického syndromu (MDS). Anémie je převládající příčinou špatné kvality života a úmrtnosti pacientů s nízkorizikovým MDS (LR-MDS). Lenalidomid byl schválen jen pro léčbu nízkorizikových del(5q) MDS po selhání účinku látek stimulujících erytropoézu (ESA), označovaných také jako erytropoézu stimulující proteiny (ESP). Ostatní pacienti s LR-MDS bez této delece jsou odkázáni po selhání účinku ESP na transfuze červených krvinek. Cílená inhibice signální dráhy TGF-β v preklinických a klinických studiích ukázala slibné výsledky. Sotatercept a jeho pozdější a účinější analog luspatercept stimulovaly erytropoézu u žen po menopauze léčených na osteoporózu a byly také účinné u specifické skupiny pacientů s MDS s prstenčitými sideroblasty, kteří přestali reagovat na ESP. Luspatercept je první inhibitor dráhy TGF-β, určený pro stimulaci pozdní fáze erytroidní diferenciace a zmírnění či odstranění anémie, který je těsně před schválením na základě slibných výsledků studií fáze III MEDALIST u LR-MDS a BELIEVE u β-thalasemie.

Transforming growth factor (TGF)-β is a cytokine originally named for its ability to transform normal fibroblasts in culture. TGF-β was subsequently found to inhibit growth of epithelial and lymphoid cells. The cellular response to TGF-β depends on the cell type and cell microenvironment. The TGF-β family includes TGF-β1, TGF-β2, TGF TGF-β3, activins A and B, nodal, myostatin, different growth differentiation factors (GDFs), the bone morphogenetic proteins (BMPs) and the anti-Műllerian hormone (AMH). More than thirty of these ligands use a far smaller number of receptors and down-stream intracellular signalling molecules. TGF-β receptor activation and phosphorylation is associated with the myelosuppression and ineffective erythropoiesis in myelodysplastic syndrome (MDS). Anaemia is the predominant cause of poor quality of life and morbidity in patients with lower-risk MDS (LR-MDS). Lenalidomide was approved only for the treatment of del(5q) MDS after failure of erythropoiesis stimulating agents (ESAs), also known as erythropoiesis stimulating proteins (ESPs). Other patients with LR-MDS have very limited therapy options after failure of ESPs and are dependent on red blood cell transfusions. Targeted inhibition of the TGF-β signalling pathway in preclinical and clinical studies showed promising results. Sotatercept and its later analogue luspater-cept stimulated erythropoiesis in postmenopausal women with osteoporosis and were also efficient in a specific group of MDS patients with ring sideroblasts who had lost their response to ESPs. Luspatercept is the first TGF-βpathway inhibitor intended for the stimulation of late stage of erythroid differentiation and for the treatment of anaemia awaiting approval on the basis of promising results of phase III studies, namely MEDALIST in RL-MDS and BELIEVE in transfusion-dependent β-thalassemia.

• Klíčová slova
• prstenčité sideroblasty, signální dráha TGF-β, sotatercept, luspatercept, galunisertib, vactosertib,
• MeSH
• anemie farmakoterapie   MeSH
• erythropoetin farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• myelodysplastické syndromy * farmakoterapie   MeSH
• protokoly protinádorové léčby MeSH
• růstové diferenciační faktory farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Acute myeloid leukemia with mutated nucleophosmin (NPMc+ AML) forms a distinct AML subgroup with better prognosis which can potentially be associated with immune response against the mutated nucleophosmin (NPM). As the T-cell-mediated immunity involves antigen presentation on HLA class I molecules, we hypothesized that individuals with suitable HLA type could be less prone to develop NPMc+ AML. We compared HLA class I distribution in NPMc+ AML patient cohort (398 patients from 5 centers) with the HLA allele frequencies of the healthy population and found HLA-A*02, B*07, B*40 and C*07 underrepresented in the NPMc+ AML group. Presence of B*07 or C*07:01 antigen was associated with better survival in patients without concomitant FLT3 internal tandem duplication. Candidate NPM-derived immunopeptides were found for B*40 and B*07 using prediction software tools. Our findings suggest that a T-cell-mediated immune response could actually explain better prognosis of NPMc+ patients and provide a rationale for attempts to explore the importance of immunosuppressive mechanisms in this AML subgroup.

• MeSH
• akutní myeloidní leukemie * genetika   imunologie   mortalita   MeSH
• buněčná imunita * MeSH
• dospělí MeSH
• jaderné proteiny * genetika   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• MHC antigeny I. třídy * genetika   imunologie   MeSH
• míra přežití MeSH
• nádorové proteiny * genetika   imunologie   MeSH
• prevalence MeSH
• přežití bez známek nemoci MeSH
• senioři MeSH
• T-lymfocyty imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lasting ≥ eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin ± prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non-del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures.

• MeSH
• erythropoetin aplikace a dávkování   terapeutické užití   MeSH
• geny p53 MeSH
• glukokortikoidy aplikace a dávkování   terapeutické užití   MeSH
• imunologické faktory aplikace a dávkování   terapeutické užití   MeSH
• indukce remise MeSH
• lenalidomid aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské chromozomy, pár 5 MeSH
• myelodysplastické syndromy farmakoterapie   genetika   MeSH
• prednison aplikace a dávkování   terapeutické užití   MeSH
• recidiva MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• 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
• Geografické názvy
• Česká republika MeSH