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1.
Blood ; 143(21): 2178-2189, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38394665

RESUMEN

ABSTRACT: Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in ∼3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, each of which has up to 10 described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL with a similar gene expression profile, poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity in the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity within and among each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions for any of the 4 tyrosine kinase genes were relatively sensitive to imatinib. In contrast, the PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with the ALL immunophenotype, 5' fusion partner, presence or absence of Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant of TKI sensitivity and relevant for specific TKI selection.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-abl , Dominios Homologos src , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Niño , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Adolescente , Preescolar , Femenino , Masculino , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Dasatinib/uso terapéutico , Dasatinib/farmacología , Proteínas de Fusión Oncogénica/genética
2.
Blood ; 143(26): 2735-2748, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38518105

RESUMEN

ABSTRACT: Acute lymphoblastic leukemia (ALL) arises from the uncontrolled proliferation of B-cell precursors (BCP-ALL) or T cells (T-ALL). Current treatment protocols obtain high cure rates in children but are based on toxic polychemotherapy. Novel therapies are urgently needed, especially in relapsed/refractory (R/R) disease, high-risk (HR) leukemias and T-ALL, in which immunotherapy approaches remain scarce. Although the interleukin-7 receptor (IL-7R) plays a pivotal role in ALL development, no IL-7R-targeting immunotherapy has yet reached clinical application in ALL. The IL-7Rα chain (CD127)-targeting IgG4 antibody lusvertikimab (LUSV; formerly OSE-127) is a full antagonist of the IL-7R pathway, showing a good safety profile in healthy volunteers. Here, we show that ∼85% of ALL cases express surface CD127. We demonstrate significant in vivo efficacy of LUSV immunotherapy in a heterogeneous cohort of BCP- and T-ALL patient-derived xenografts (PDX) in minimal residual disease (MRD) and overt leukemia models, including R/R and HR leukemias. Importantly, LUSV was particularly effective when combined with polychemotherapy in a phase 2-like PDX study with CD127high samples leading to MRD-negativity in >50% of mice treated with combination therapy. Mechanistically, LUSV targeted ALL cells via a dual mode of action comprising direct IL-7R antagonistic activity and induction of macrophage-mediated antibody-dependent cellular phagocytosis (ADCP). LUSV-mediated in vitro ADCP levels significantly correlated with CD127 expression levels and the reduction of leukemia burden upon treatment of PDX animals in vivo. Altogether, through its dual mode of action and good safety profile, LUSV may represent a novel immunotherapy option for any CD127+ ALL, particularly in combination with standard-of-care polychemotherapy.


Asunto(s)
Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Humanos , Ratones , Receptores de Interleucina-7/antagonistas & inhibidores , Ratones SCID , Fagocitosis/efectos de los fármacos , Subunidad alfa del Receptor de Interleucina-7 , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Femenino , Ratones Endogámicos NOD , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Línea Celular Tumoral , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico
3.
Blood ; 144(1): 74-83, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38588489

RESUMEN

ABSTRACT: Pediatric B-cell precursor (BCP) lymphoblastic malignancies are neoplasms with manifestation either in the bone marrow or blood (BCP acute lymphoblastic leukemia [BCP-ALL]) or are less common in extramedullary tissue (BCP lymphoblastic lymphoma [BCP-LBL]). Although both presentations are similar in morphology and immunophenotype, molecular studies have been virtually restricted to BCP-ALL so far. The lack of molecular studies on BCP-LBL is due to its rarity and restriction on small, mostly formalin-fixed paraffin-embedded (FFPE) tissues. Here, to our knowledge, we present the first comprehensive mutational and transcriptional analysis of what we consider the largest BCP-LBL cohort described to date (n = 97). Whole-exome sequencing indicated a mutational spectrum of BCP-LBL, strikingly similar to that found in BCP-ALL. However, epigenetic modifiers were more frequently mutated in BCP-LBL, whereas BCP-ALL was more frequently affected by mutation in genes involved in B-cell development. Integrating copy number alterations, somatic mutations, and gene expression by RNA sequencing revealed that virtually all molecular subtypes originally defined in BCP-ALL are present in BCP-LBL, with only 7% of lymphomas that were not assigned to a subtype. Similar to BCP-ALL, the most frequent subtypes of BCP-LBL were high hyperdiploidy and ETV6::RUNX1. Tyrosine kinase/cytokine receptor rearrangements were detected in 7% of BCP-LBL. These results indicate that genetic subtypes can be identified in BCP-LBL using next-generation sequencing, even in FFPE tissue, and may be relevant to guide treatment.


Asunto(s)
Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Masculino , Preescolar , Femenino , Adolescente , Lactante , Secuenciación del Exoma , Transcripción Genética
4.
Genes Chromosomes Cancer ; 63(1): e23217, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38087879

RESUMEN

A common finding in pediatric B-cell precursor acute lymphoblastic leukemia (BCPALL) is that chromosome 21 is never lost and an extra chromosome 21 is often gained. This implies an important role for chromosome 21 in the pathobiology of BCPALL, emphasized by the increased risk of BCPALL in children with Down syndrome. However, model systems of chromosome 21 gain are lacking. We therefore developed a BCPALL cell line (Nalm-6, DUX4-rearranged) with an additional chromosome 21 by means of microcell-mediated chromosome transfer. FISH, PCR, multiplex ligation-dependent probe amplification, and whole exome sequencing showed that an additional chromosome 21 was successfully transferred to the recipient cells. Transcription of some but not all genes on chromosome 21 was increased, indicating tight transcriptional regulation. Nalm-6 cells with an additional chromosome 21 proliferated slightly slower compared with parental Nalm-6 and sensitivity to induction chemotherapeutics was mildly increased. The extra copy of chromosome 21 did not confer sensitivity to targeted signaling inhibitors. In conclusion, a BCPALL cell line with an additional human chromosome 21 was developed, validated, and subjected to functional studies, which showed a minor but potentially relevant effect in vitro. This cell line offers the possibility to study further the role of chromosome 21 in ALL.


Asunto(s)
Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Niño , Cromosomas Humanos Par 21/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Reacción en Cadena de la Polimerasa
5.
Haematologica ; 109(7): 2073-2084, 2024 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-38426282

RESUMEN

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSC) mimic this protective environment in ex vivo co-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flow-sorted MSC after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSC, which was partially dependent on direct cell-cell signaling. The signature was selectively induced by BCP-ALL cells, most profoundly by ETV6-RUNX1-positive ALL cells, as co-culture of MSC with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSC both secreted IFNα and IFNß, but not IFNγ. In line, the IFN gene signature was sensitive to blockade of IFNα/ß signaling, but less to that of IFNγ. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFNα/ß inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFNα/ß-related genes by MSC does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL.


Asunto(s)
Técnicas de Cocultivo , Interferón-alfa , Interferón beta , Células Madre Mesenquimatosas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Interferón-alfa/farmacología , Interferón beta/metabolismo , Microambiente Tumoral , Transducción de Señal , Niño , Línea Celular Tumoral , Transcriptoma , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Regulación Leucémica de la Expresión Génica , Proteína ETS de Variante de Translocación 6 , Subunidad alfa 2 del Factor de Unión al Sitio Principal
6.
Haematologica ; 2024 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-39385738

RESUMEN

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C as a key factor for B-ALL development and maintenance. While cyclin C is non-essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1+ cells resulting in the incapability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

7.
Blood ; 138(20): 1953-1965, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-34098582

RESUMEN

We previously identified an association of rapid engraftment of patient-derived leukemia cells transplanted into NOD/SCID mice with early relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In a search for the cellular and molecular profiles associated with this phenotype, we investigated the expression of microRNAs (miRNAs) in different engraftment phenotypes and patient outcomes. We found high expression of miR-497 and miR-195 (hereafter miR-497/195) in patient-derived xenograft samples with slow engraftment derived from patients with favorable outcome. In contrast, epigenetic repression and low expression of these miRNAs was observed in rapidly engrafting samples associated with early relapse. Overexpression of miR-497/195 in patient-derived leukemia cells suppressed in vivo growth of leukemia and prolonged recipient survival. Conversely, inhibition of miR-497/195 led to increased leukemia cell growth. Key cell cycle regulators were downregulated upon miR-497/195 overexpression, and we identified cyclin-dependent kinase 4 (CDK4)- and cyclin-D3 (CCND3)-mediated control of G1/S transition as a principal mechanism for the suppression of BCP-ALL progression by miR-497/195. The critical role for miR-497/195-mediated cell cycle regulation was underscored by finding (in an additional independent series of patient samples) that high expression of miR-497/195 together with a full sequence for CDKN2A and CDKN2B (CDKN2A/B) was associated with excellent outcome, whereas deletion of CDKN2A/B together with low expression of miR-497/195 was associated with clearly inferior relapse-free survival. These findings point to the cooperative loss of cell cycle regulators as a new prognostic factor indicating possible therapeutic targets for pediatric BCP-ALL.


Asunto(s)
Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animales , Niño , Epigénesis Genética , Regulación Leucémica de la Expresión Génica , Humanos , Ratones Endogámicos NOD , Ratones SCID , Células Tumorales Cultivadas
8.
Blood ; 137(12): 1582-1590, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33067614

RESUMEN

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Inotuzumab Ozogamicina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Antineoplásicos Inmunológicos/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Inotuzumab Ozogamicina/efectos adversos , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Resultado del Tratamiento
9.
Blood ; 136(3): 313-327, 2020 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-32321174

RESUMEN

B-cell acute lymphoblastic leukemia (ALL; B-ALL) is the most common pediatric cancer, and high hyperdiploidy (HyperD) identifies the most common subtype of pediatric B-ALL. Despite HyperD being an initiating oncogenic event affiliated with childhood B-ALL, the mitotic and chromosomal defects associated with HyperD B-ALL (HyperD-ALL) remain poorly characterized. Here, we have used 54 primary pediatric B-ALL samples to characterize the cellular-molecular mechanisms underlying the mitotic/chromosome defects predicated to be early pathogenic contributors in HyperD-ALL. We report that HyperD-ALL blasts are low proliferative and show a delay in early mitosis at prometaphase, associated with chromosome-alignment defects at the metaphase plate leading to robust chromosome-segregation defects and nonmodal karyotypes. Mechanistically, biochemical, functional, and mass-spectrometry assays revealed that condensin complex is impaired in HyperD-ALL cells, leading to chromosome hypocondensation, loss of centromere stiffness, and mislocalization of the chromosome passenger complex proteins Aurora B kinase (AURKB) and Survivin in early mitosis. HyperD-ALL cells show chromatid cohesion defects and an impaired spindle assembly checkpoint (SAC), thus undergoing mitotic slippage due to defective AURKB and impaired SAC activity, downstream of condensin complex defects. Chromosome structure/condensation defects and hyperdiploidy were reproduced in healthy CD34+ stem/progenitor cells upon inhibition of AURKB and/or SAC. Collectively, hyperdiploid B-ALL is associated with a defective condensin complex, AURKB, and SAC.


Asunto(s)
Adenosina Trifosfatasas , Aurora Quinasa B , Aberraciones Cromosómicas , Cromosomas Humanos , Proteínas de Unión al ADN , Metafase/genética , Complejos Multiproteicos , Proteínas de Neoplasias , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Cromosomas Humanos/genética , Cromosomas Humanos/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética
10.
Blood ; 135(17): 1438-1446, 2020 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-32315382

RESUMEN

Risk stratification is essential for the delivery of optimal treatment in childhood acute lymphoblastic leukemia. However, current risk stratification algorithms dichotomize variables and apply risk factors independently, which may incorrectly assume identical associations across biologically heterogeneous subsets and reduce statistical power. Accordingly, we developed and validated a prognostic index (PIUKALL) that integrates multiple risk factors and uses continuous data. We created discovery (n = 2405) and validation (n = 2313) cohorts using data from 4 recent trials (UKALL2003, COALL-03, DCOG-ALL10, and NOPHO-ALL2008). Using the discovery cohort, multivariate Cox regression modeling defined a minimal model including white cell count at diagnosis, pretreatment cytogenetics, and end-of-induction minimal residual disease. Using this model, we defined PIUKALL as a continuous variable that assigns personalized risk scores. PIUKALL correlated with risk of relapse and was validated in an independent cohort. Using PIUKALL to risk stratify patients improved the concordance index for all end points compared with traditional algorithms. We used PIUKALL to define 4 clinically relevant risk groups that had differential relapse rates at 5 years and were similar between the 2 cohorts (discovery: low, 3% [95% confidence interval (CI), 2%-4%]; standard, 8% [95% CI, 6%-10%]; intermediate, 17% [95% CI, 14%-21%]; and high, 48% [95% CI, 36%-60%; validation: low, 4% [95% CI, 3%-6%]; standard, 9% [95% CI, 6%-12%]; intermediate, 17% [95% CI, 14%-21%]; and high, 35% [95% CI, 24%-48%]). Analysis of the area under the curve confirmed the PIUKALL groups were significantly better at predicting outcome than algorithms employed in each trial. PIUKALL provides an accurate method for predicting outcome and more flexible method for defining risk groups in future studies.


Asunto(s)
Biomarcadores de Tumor/análisis , Recurrencia Local de Neoplasia/patología , Neoplasia Residual/patología , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Selección de Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Adolescente , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/terapia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia
11.
EMBO J ; 36(6): 718-735, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28219927

RESUMEN

PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from the Pax5 locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6+ B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.


Asunto(s)
Proteínas Oncogénicas/metabolismo , Factor de Transcripción PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Proteínas Proto-Oncogénicas c-ets/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/metabolismo , Animales , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Ratones , Proteínas Oncogénicas/genética , Factor de Transcripción PAX5/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Represoras/genética , Proteína ETS de Variante de Translocación 6
12.
Br J Haematol ; 194(5): 888-892, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34337744

RESUMEN

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5-10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases.


Asunto(s)
Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Niño , Eliminación de Gen , Humanos , Neoplasia Residual/genética , Fusión de Oncogenes , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
13.
Haematologica ; 104(4): 738-748, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30381299

RESUMEN

Translocation t(12;21), resulting in the ETV6-RUNX1 (or TEL-AML1) fusion protein, is present in 25% of pediatric patients with B-cell precursor acute lymphoblastic leukemia and is considered a first hit in leukemogenesis. A targeted therapy approach is not available for children with this subtype of leukemia. To identify the molecular mechanisms underlying ETV6-RUNX1-driven leukemia, we performed gene expression profiling of healthy hematopoietic progenitors in which we ectopically expressed ETV6-RUNX1. We reveal an ETV6-RUNX1-driven transcriptional network that induces proliferation, survival and cellular homeostasis. In addition, Vps34, an important regulator of autophagy, was found to be induced by ETV6-RUNX1 and up-regulated in ETV6-RUNX1-positive leukemic patient cells. We show that induction of Vps34 was transcriptionally regulated by ETV6-RUNX1 and correlated with high levels of autophagy. Knockdown of Vps34 in ETV6-RUNX1-positive cell lines severely reduced proliferation and survival. Inhibition of autophagy by hydroxychloroquine, a well-tolerated autophagy inhibitor, reduced cell viability in both ETV6-RUNX1-positive cell lines and primary acute lymphoblastic leukemia samples, and selectively sensitized primary ETV6-RUNX1-positive leukemia samples to L asparaginase. These findings reveal a causal relationship between ETV6-RUNX1 and autophagy, and provide pre-clinical evidence for the efficacy of autophagy inhibitors in ETV6-RUNX1-driven leukemia.


Asunto(s)
Asparaginasa/farmacología , Muerte Celular Autofágica/efectos de los fármacos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Sistemas de Liberación de Medicamentos , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Muerte Celular Autofágica/genética , Niño , Preescolar , Fosfatidilinositol 3-Quinasas Clase III/genética , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología
14.
Br J Haematol ; 180(4): 550-562, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29194562

RESUMEN

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8-CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10-5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 +  for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 +  groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.


Asunto(s)
Deleción Cromosómica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Eliminación de Secuencia , Adolescente , Factores de Edad , Biomarcadores de Tumor , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Recurrencia , Medición de Riesgo , Factores de Riesgo
16.
Blood ; 128(7): 911-22, 2016 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-27229005

RESUMEN

Somatic genetic abnormalities are initiators and drivers of disease and have proven clinical utility at initial diagnosis. However, the genetic landscape and its clinical utility at relapse are less well understood and have not been studied comprehensively. We analyzed cytogenetic data from 427 children with relapsed B-cell precursor ALL treated on the international trial, ALLR3. Also we screened 238 patients with a marrow relapse for selected copy number alterations (CNAs) and mutations. Cytogenetic risk groups were predictive of outcome postrelapse and survival rates at 5 years for patients with good, intermediate-, and high-risk cytogenetics were 68%, 47%, and 26%, respectively (P < .001). TP53 alterations and NR3C1/BTG1 deletions were associated with a higher risk of progression: hazard ratio 2.36 (95% confidence interval, 1.51-3.70, P < .001) and 2.15 (1.32-3.48, P = .002). NRAS mutations were associated with an increased risk of progression among standard-risk patients with high hyperdiploidy: 3.17 (1.15-8.71, P = .026). Patients classified clinically as standard and high risk had distinct genetic profiles. The outcome of clinical standard-risk patients with high-risk cytogenetics was equivalent to clinical high-risk patients. Screening patients at relapse for key genetic abnormalities will enable the integration of genetic and clinical risk factors to improve patient stratification and outcome. This study is registered at www.clinicaltrials.org as #ISCRTN45724312.


Asunto(s)
Predisposición Genética a la Enfermedad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Niño , Preescolar , Aberraciones Cromosómicas , Estudios de Cohortes , Análisis Citogenético , Variaciones en el Número de Copia de ADN/genética , Demografía , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Mutación/genética , Pronóstico , Recurrencia , Factores de Riesgo
18.
Blood ; 126(21): 2404-14, 2015 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-26297738

RESUMEN

Acute lymphoblastic leukemia (ALL) cells reside in the bone marrow microenvironment which nurtures and protects cells from chemotherapeutic drugs. The disruption of cell-cell communication within the leukemic niche may offer an important new therapeutic strategy. Tunneling nanotubes (TNTs) have been described as a novel mode of intercellular communication, but their presence and importance in the leukemic niche are currently unknown. Here, we show for the first time that primary B-cell precursor ALL (BCP-ALL) cells use TNTs to signal to primary mesenchymal stromal cells (MSCs). This signaling results in secretion of prosurvival cytokines, such as interferon-γ-inducible protein 10/CXC chemokine ligand 10, interleukin 8, and monocyte chemotactic protein-1/CC chemokine ligand 2. A combination of TNT-disrupting conditions allows us to analyze the functional importance of TNTs in an ex vivo model. Our results indicate that TNT signaling is important for the viability of patient-derived B-cell precursor ALL cells and induces stroma-mediated prednisolone resistance. Disruption of TNTs significantly inhibits these leukemogenic processes and resensitizes B-cell precursor ALL cells to prednisolone. Our findings establish TNTs as a novel communication mechanism by which ALL cells modulate their bone marrow microenvironment. The identification of TNT signaling in ALL-MSC communication gives insight into the pathobiology of ALL and opens new avenues to develop more effective therapies that interfere with the leukemic niche.


Asunto(s)
Comunicación Celular , Resistencia a Antineoplásicos , Células Madre Mesenquimatosas/metabolismo , Nanotubos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Microambiente Tumoral , Adolescente , Línea Celular Tumoral , Niño , Preescolar , Citocinas/metabolismo , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Prednisolona/farmacología
19.
Blood ; 125(8): 1282-91, 2015 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-25515960

RESUMEN

PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5-JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis.


Asunto(s)
Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación Leucémica de la Expresión Génica , Células HEK293 , Células HeLa , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/metabolismo , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción STAT/metabolismo , Transcriptoma , Células Tumorales Cultivadas
20.
Haematologica ; 102(3): 541-551, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27979924

RESUMEN

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/- mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/- displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.


Asunto(s)
Transformación Celular Neoplásica/genética , Epistasis Genética , Factor de Transcripción Ikaros/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Animales , Biomarcadores de Tumor , Transformación Celular Neoplásica/metabolismo , Niño , Preescolar , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Humanos , Factor de Transcripción Ikaros/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas de Neoplasias/metabolismo , Evaluación del Resultado de la Atención al Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Recurrencia , Proteínas Supresoras de Tumor/metabolismo
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