Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.

• MeSH
• anaplastická lymfomová kináza * metabolismus   genetika   MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   patologie   genetika   metabolismus   MeSH
• benzamidy farmakologie   MeSH
• histondeacetylasa 1 * genetika   antagonisté a inhibitory   fyziologie   metabolismus   MeSH
• histondeacetylasa 2 genetika   MeSH
• inhibitory histondeacetylas * farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• pyridiny farmakologie   MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Alk protein, mouse MeSH Prohlížeč
• anaplastická lymfomová kináza * MeSH
• benzamidy MeSH
• entinostat MeSH Prohlížeč
• Hdac1 protein, mouse MeSH Prohlížeč
• histondeacetylasa 1 * MeSH
• histondeacetylasa 2 MeSH
• inhibitory histondeacetylas * MeSH
• pyridiny MeSH

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non-small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

• MeSH
• anaplastická lymfomová kináza MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   genetika   patologie   MeSH
• endoteliální buňky metabolismus   MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• inhibitory tyrosinkinasy MeSH
• krizotinib farmakologie   terapeutické užití   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   MeSH
• receptory CCR7 genetika   MeSH
• tyrosinkinasové receptory metabolismus   MeSH
• tyrosinkinasy MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• CCR7 protein, human MeSH Prohlížeč
• fosfatidylinositol-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• inhibitory tyrosinkinasy MeSH
• krizotinib MeSH
• receptory CCR7 MeSH
• tyrosinkinasové receptory MeSH
• tyrosinkinasy MeSH

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

• Klíčová slova
• ALCL, Apoptosis, NPM-ALK, PDGFRβ, STAT3, STAT5A, STAT5B,
• MeSH
• anaplastická lymfomová kináza MeSH
• anaplastický velkobuněčný lymfom * genetika   patologie   MeSH
• fosforylace MeSH
• karcinogeneze metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• růstový faktor odvozený z trombocytů - receptor beta * metabolismus   farmakologie   MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• transkripční faktor STAT5 * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• růstový faktor odvozený z trombocytů - receptor beta * MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 * MeSH
• transkripční faktor STAT5 * MeSH

• MeSH
• aminopyridiny MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   MeSH
• laktamy MeSH
• lidé MeSH
• makrocyklické laktamy MeSH
• pyrazoly terapeutické užití   MeSH
• reziduální nádor MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminopyridiny MeSH
• laktamy MeSH
• lorlatinib MeSH Prohlížeč
• makrocyklické laktamy MeSH
• pyrazoly MeSH

Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.

• MeSH
• anaplastická lymfomová kináza antagonisté a inhibitory   metabolismus   MeSH
• anaplastický velkobuněčný lymfom farmakoterapie   metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• krizotinib farmakologie   MeSH
• lidé MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• protinádorové látky farmakologie   MeSH
• tyrosinfosfatasa nereceptorového typu 1 metabolismus   MeSH
• tyrosinfosfatasa nereceptorového typu 2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ALK protein, human MeSH Prohlížeč
• anaplastická lymfomová kináza MeSH
• inhibitory proteinkinas MeSH
• krizotinib MeSH
• protinádorové látky MeSH
• tyrosinfosfatasa nereceptorového typu 1 MeSH
• tyrosinfosfatasa nereceptorového typu 2 MeSH

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• Klíčová slova
• anaplastic large cell lymphoma, chemotherapy, nucleophosmin1-anaplastic lymphoma kinase, paediatric cancer, resistance,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

• MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• receptor Notch1 genetika   MeSH
• sekvenování exomu MeSH
• tyrosinkinasové receptory genetika   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• NOTCH1 protein, human MeSH Prohlížeč
• receptor Notch1 MeSH
• tyrosinkinasové receptory MeSH
• tyrosinkinasy MeSH

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

• MeSH
• anaplastický velkobuněčný lymfom farmakoterapie   genetika   metabolismus   patologie   MeSH
• biologické modely MeSH
• buněčné linie MeSH
• chemorezistence genetika   MeSH
• CRISPR-Cas systémy MeSH
• editace genu MeSH
• exprese genu MeSH
• imunohistochemie MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• krizotinib farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nukleofosmin MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• receptor interleukinu-10 - alfa-podjednotka genetika   metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• tyrosinkinasy genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory proteinkinas MeSH
• krizotinib MeSH
• NPM1 protein, human MeSH Prohlížeč
• nukleofosmin MeSH
• p80(NPM-ALK) protein MeSH Prohlížeč
• protinádorové látky MeSH
• receptor interleukinu-10 - alfa-podjednotka MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 MeSH
• tyrosinkinasy MeSH