Molecular-cytogenetic analysis of aggressive lymphomas

• Název práce v češtině: Molekulárně-cytogenetická analýza agresivních lymfomů
• Název v anglickém jazyce: Molecular-cytogenetic analysis of aggressive lymphomas
• Klíčová slova: agresivní lymfomy, lymfom z buněk pláště, genetická krajina, klonální vývoj, xenografty odvozené od pacientů
• Klíčová slova anglicky: aggressive lymphomas, mantle cell lymphoma, genomic landscape, clonal development, patient-derived xenografts
• Akademický rok vypsání: 2016/2017
• Typ práce: disertační práce
• Jazyk práce: angličtina
• Ústav: Ústav patologické fyziologie 1. LF UK (11-00180)
• Vedoucí / školitel: prof. MUDr. Pavel Klener, Ph.D.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 13.10.2016
• Datum zadání: 13.10.2016
• Datum potvrzení stud. oddělením: 13.10.2016
• Datum a čas obhajoby: 18.12.2025 10:00
• Místo konání obhajoby: Fyziologický ústav 1. LF UK
• Datum odevzdání elektronické podoby: 07.10.2025
• Datum proběhlé obhajoby: 18.12.2025
• Předmět: Obhajoba dizertační práce (B90002)
• Oponenti: doc. MUDr. Pavel Otáhal, Ph.D.

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Předběžná náplň práce

Lymfom z buněk pláště (MCL) zůstává nadále jedním z nejobtížněji léčitelných B-buněčných lymfomů, který se vyznačuje častými relapsy a nepříznivým průběhem. Zejména vysoce rizikoví, relabující a refrakterní pacienti naléhavě potřebují efektivnější terapeutické přístupy. Současná míra poznání genetického profilu a klonálního vývoje u relabujících pacientů, jež by mohla vést ke zlepšení prognózy těchto pacientů, je stále nedostatečná. Skupina agresivních non-hodgkinských lymfomů (NHL), kam patří i MCL, rovněž postrádá dostatečně efektivní preklinické modely, jejichž komplexní charakterizace je zásadní pro vývoj spolehlivých experimentálních systémů a poznání biologie choroby.
Naše celoexomová analýza 25 párových vzorků, získaných od pacientů s MCL a odebraných při stanovení diagnózy a při relapsu po standardní imunochemoterapii, prokázala významnou klonální evoluci během progrese onemocnění. Rezistentní (sub)klony, obohacené o závažné genetické aberace, zejména inaktivace genů TP53 a CDKN2A, byly s největší pravděpodobností přítomny již v době diagnózy a následně selektovány léčbou. V relapsu vykazovaly tyto klony vyšší genetickou heterogenitu, vyjádřenou zvýšenou mutační náloží, rozsáhlejší a početnější změny v množství genových kopií, a výrazně vyšší alelické frekvence mutací TP53. Identifikovali jsme rovněž potenciální nové kandidátní geny spojené s relapsem, mimo jiné LRP1B, KMT2D, SP140, NOTCH1/2, PIK3CA a GNA14, což poukazuje na komplexní klonální dynamiku a naznačuje možné biologické mechanismy rezistence. Tato zjištění současně podtrhují omezenou účinnost současné chemoimunoterapie u pacientů s inaktivací TP53 a CDKN2A a podporují časné zařazení inovativních léčebných strategií, jako je imunoterapie s geneticky modifikovanými autologními T-lymfocyty, u této vysoce rizikové skupiny.
Současně jsme provedli detailní charakterizaci 15 nově vyvinutých myších modelů (PDX) odvozených od pacientů s agresivními lymfomy, reprezentovanými lymfomem z buněk pláště, difuzním velkobuněčným B-lymfomem, Burkittovým lymfomem a T-buněčnými lymfomy. Celoexomová analýza potvrdila, že PDX modely věrně kopírují genetický profil původních lymfomů, včetně mutačního spektra a změn počtu genových kopií. Podrobná histopatologická analýza však odhalila některé fenotypové odlišnosti. PDX nádory vykazovaly agresivnější morfologii, vyšší proliferační aktivitu a významnou ztrátu homogenity nádorového mikroprostředí. V rámci analýzy nebyly detekovány lidské nemaligní imunitní buňky, nádory rovněž postrádaly infiltraci myšími makrofágy, a vaskularizace byla tvořena pouze myšími cévami s výrazně nižší hustotou a plochou cév ve srovnání s původními biopsiemi. Tyto rozdíly ukazují, že ačkoliv jsou PDX modely mimořádně cenným translačním nástrojem, vykazují menší závislost na lidských složkách mikroprostředí a jejich využití by proto mělo být posuzováno s opatrností zejména ve studiích zaměřených na angiogenezi, imunitní odpověď či terapie, cílící na mikroprostředí.
Obě výše zmíněné studie, detailně popsané v této práci, tak rozšiřují naše poznání patogeneze agresivních lymfomů, v čele s MCL, a přinášejí klíčové podněty pro jejich další translační výzkum. Ukazují, jak chemoimmunoterapie formuje klonální vývoj selekcí geneticky komplexních a terapii odolných subklonů, a svým klinickým přesahem podtrhují potřebu zařazení nových terapeutických strategií již v úvodu léčby. Současně dokládají, že PDX modely jsou sice nepostradatelným, avšak ne zcela bezchybným nástrojem, který věrně zachovává zásadní genetické charakteristiky agresivních lymfomů, a to i přes změny v nádorovém mikroprostředí. Studie tak zdůrazňuje jejich přednosti i limity v preklinickém a klinickém výzkumu. Celkově tato práce poskytuje řadu nových patofyziologických poznatků o genetickém prostředí MCL a pevný základ pro zdokonalení rizikové stratifikace této choroby. Rovněž dokládá vysokou relevanci experimentálních modelů v translačním a klinickém výzkumu, s konečným cílem urychlit vývoj účinnějších terapií pro agresivní lymfomy.

Předběžná náplň práce v anglickém jazyce

Mantle cell lymphoma (MCL) remains one of the most challenging B-cell lymphomas, known for frequent relapses and poor outcomes in high-risk subgroups. Information about the clonal development of MCL and the genomic landscape of relapsed patients with MCL is still scarce, and such patients are in urgent need of more sophisticated therapies. Additionally, a group of aggressive non-Hodgkin lymphomas (NHLs) still lacks sufficiently effective preclinical models, and their complex characterization is of utmost importance for developing reliable experimental models.
Our whole-exome sequencing study of 25 paired diagnostic and relapse samples from MCL patients treated with standard immunochemotherapy revealed significant clonal evolution during disease progression. Resistant subclones, which were enriched for harmful genetic lesions such as TP53 and CDKN2A inactivation, were likely present at diagnosis and were selected by therapy. At relapse, these clones exhibited increased genetic diversity, characterized by a higher mutation load, more extensive and numerous copy number alterations, and notably higher variant allele frequencies of TP53 mutations. We also identified new relapse-associated candidate drivers, including LRP1B, KMT2D, SP140, NOTCH1/2, PIK3CA, and GNA14, which highlights the complexity of clonal dynamics and points to potential biological mediators of resistance. These results also underscore the limited effectiveness of chemotherapy in patients with TP53 and CDKN2A inactivation and support early consideration of innovative treatments, such as genetically engineered T-cell immunotherapies, for this high-risk group.
In parallel, we performed a detailed characterization of 15 newly developed patient-derived xenograft (PDX) models of aggressive lymphomas, including MCL, Diffuse Large B-cell Lymphoma, Burkitt lymphoma, and T-cell lymphomas. Whole-exome sequencing confirmed that PDX models accurately preserved the genetic profiles of the original lymphomas, maintaining both mutational patterns and copy number variations. However, detailed histopathological analyses revealed consistent phenotypic differences. PDX tumors showed more aggressive morphology, higher proliferation rates, and a significant reduction in tumor microenvironment (TME) complexity. Notably, human non-malignant immune cells were absent, murine macrophages did not infiltrate the tumors, and vascularization was limited to murine vessels with significantly decreased microvessel density and area compared to the original biopsies. These differences highlight that, while PDXs are highly relevant translational tools, they portray tumors with reduced dependence on human TME components and should be interpreted with caution in studies focusing on angiogenesis, immune responses, or therapies that depend on the microenvironment.
Taken together, these two complementary studies enhance our understanding of MCL pathogenesis and offer crucial insights for translational lymphoma research. They show how chemotherapy influences clonal evolution by selecting for genetically complex, therapy-resistant subclones, highlighting the need to incorporate new therapeutic strategies into initial treatment plans. Additionally, they demonstrate that PDX models are valuable yet imperfect tools that retain the key genetic features of aggressive lymphomas, albeit in a different microenvironmental context, highlighting both their advantages and limitations for preclinical and clinical studies. Overall, this work offers novel insights into the pathophysiology of MCL and provides a strong foundation for enhancing risk stratification in MCL. Additionally, it increases the translational relevance of experimental models, ultimately supporting the development of more effective treatments for aggressive lymphomas.