Acute lymphoblastic leukemia (ALL)

  • Ribera Group_04_2018
Campus ICO-Germans Trias i Pujol

Josep Carreras Leukaemia Research Institute
Edifici IMPPC
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

 

Directions

Summary

Our research is focused on Acute lymphoblastic Leukemia (ALL) disease, including B-cell precursor and T-precursor ALL. We want to resolve questions that require a full range of research from from basic to clinical. We aim to provide the physician with new tools, by using basic research data that will have an impact on healthcare, in order to improve survival rates in patients with this type of leukaemia.

Research

Acute Lymphoblastic Leukemia is still a non-curable neoplasia mainly in adult patients. The survival rates for ALL are much lower in adults than in children. The reasons for this survival difference lie largely in the higher frequency of poor prognosis subtypes of ALL in adults and a poorer tolerance of the treatment as age increases. Except for selected subgroups (i.e., Ph+ ALL), the current therapeutic protocols for ALL do not take into account the differences in the molecular background of the disease, and few new alternative therapies are only available in refractory or resistant ALL. Therefore, if we want to improve the survival of patients with ALL we first need to obtain detailed and relevant molecular information to enable doctors to accurately define the risk and decide on the treatment. Secondly, we need to have specific therapeutic alternatives available to apply to these new oncogenetic ALL subgroups.

Main Research Lines:

The current research of the group at the IJC Institute can be divided in two main areas:

1: Clinical research: Design and analysis of the results of the Spanish treatment protocols on adult ALL in the setting of the Spanish PETHEMA group (Programa Español de Tratamientos en Hematología).

2. Biologic and translational research

The ALL Group is currently evaluating the frequency and prognostic significance of new genetic markers in B- and T- lineage ALL. The results of this study, which are in line with the results found by other ALL working groups, will be applied in the new therapeutic protocols in ALL of the PETHEMA group.

In addition, we want to assess the anti-leukemic effect of the available drugs that specifically target candidate genes in an in vivo model. We also want to check if copy number alterations (CNAs) identified in other blood neoplasias such as; Acute Myeloblastic Leukaemia (AML), Non-Hodgkin Lymphoma (NHL) and Chronic Myeloid Leukaemia (CLL), or in solid cancers such as Melanoma and Breast Cancer, could also have an impact on ALL. We expect that the results obtained, will be used to re-classify ALL patients into different oncogenetic subgroups according to the predicted treatment response and the specific target therapy to be applied.

The identification of clonal heterogeneity in ALL at the time of diagnosis has introduced a high order of complexity to the disease. It is this clonal heterogeneity that is responsible for patient’s relapses, in which treatment has failed. Future projects in the group will be focused on the characterization of leukemic cells resistant to treatment using a genetic and functional approach.

Collaborations

People

Selected publications

Ribera JM

Therapy-related acute lymphoblastic leukemia.

Haematologica Oct 2018, 103 (10) 1581-1583. More information
Gachet S, El-Chaar T, Avran D, Genesca E, Catez F, Quentin S, Delord M, Thérizols G, Briot D, Meunier G, Hernandez L, Pla M, Smits WK, Buijs-Gladdines JG, Van Loocke W, Menschaert G, André-Schmutz I, Taghon T, Van Vlierberghe P, Meijerink JP, Baruchel A, Dombret H, Clappier E, Diaz JJ, Gazin C, de Thé H, Sigaux F, Soulier J

Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.

Cancer Discov Dec 2018, 8 (12) 1614-1631. Epub 28 Sep 2018
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14,
More information
Genescà E, Lazarenkov A, Morgades M, Berbis G, Ruíz-Xivillé N, Gómez-Marzo P, Ribera J, Juncà J, González-Pérez A, Mercadal S, Guardia R, Artola MT, Moreno MJ, Martínez-López J, Zamora L, Barba P, Gil C, Tormo M, Cladera A, Novo A, Pratcorona M, Nomdedeu J, González-Campos J, Almeida M, Cervera J, Montesinos P, Batlle M, Vives S, Esteve J, Feliu E, Solé F, Orfao A, Ribera JM

Frequency and clinical impact of CDKN2A/ARF/CDKN2B gene deletions as assessed by in-depth genetic analyses in adult T cell acute lymphoblastic leukemia.

J Hematol Oncol 24 Jul 2018, 11 (1) 96. Epub 24 Jul 2018
Recurrent deletions of the CDKN2A/ARF/CDKN2B genes encoded at chromosome 9p21 have been described in both pediatric and adult acute lymphoblastic leukemia (ALL), but their prognostic value remains controversial, with limited data on adult T-ALL. Here, we investigated the presence of homozygous and heterozygous deletions of the CDKN2A/ARF and CDKN2B genes in 64 adult T-ALL patients enrolled in two consecutive trials from the Spanish PETHEMA group. Alterations in CDKN2A/ARF/CDKN2B were detected in 35/64 patients (55%). Most of them consisted of 9p21 losses involving homozygous deletions of the CDKNA/ARF gene (26/64), as confirmed by single nucleotide polymorphism (SNP) arrays and interphase fluorescence in situ hybridization (iFISH). Deletions involving the CDKN2A/ARF/CDKN2B locus correlated with a higher frequency of cortical T cell phenotype and a better clearance of minimal residual disease (MRD) after induction therapy. Moreover, the combination of an altered copy-number-value (CNV) involving the CDKN2A/ARF/CDKN2B gene locus and undetectable MRD (≤ 0.01%) values allowed the identification of a subset of T-ALL with better overall survival in the absence of hematopoietic stem cell transplantation.
More information
Buatois V, Johnson Z, Salgado-Pires S, Papaioannou A, Hatterer E, Chauchet X, Richard F, Barba L, Daubeuf B, Cons L, Broyer L, D'Asaro M, Matthes T, LeGallou S, Fest T, Tarte K, Clarke Hinojosa RK, Genescà Ferrer E, Ribera JM, Dey A, Bailey K, Fielding AK, Eissenberg L, Ritchey J, Rettig M, DiPersio JF, Kosco-Vilbois MH, Masternak K, Fischer N, Shang L, Ferlin WG

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia.

Mol. Cancer Ther. Aug 2018, 17 (8) 1739-1751. Epub 9 May 2018
CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent
More information
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Current projects

Comparison of next generation sequencing (NGS) and high sensitivity citometry to asses minimal residual disease (MRD) in childhood and adult acute lymphoblastic leukemia

Project leader:José María Ribera
Code:PI14/01971
Funding:
Start date:01/01/2015
End date:31/12/2017

Identification of copy number alterations as targets for available drugs involved in T-ALL leukemogenesis and prognosis

Project leader:Eulàlia Genesca
Code:CELGENE T-ALL
Funding:
Start date:01/01/2014
End date:31/12/2016

Exploring Mechanisms of Resistance in Adult and Pediatric T-Acute Lymphoblastic Leukemia;(A.Bigas,IMIM)&(J.M.Ribera-E.Genescà,IJC)

Project leader:José María Ribera
Code:GC16173697BIGA
Funding:
Start date:01/11/2016
End date:31/10/2021

HARMONY Healthcare Alliance for Resourceful Medicines Offensive against Neoplasms in hematology

Project leader:José María Ribera
Code:116026 HARMONY H2020 JTI-IMI2 2015-06
Funding:
Start date:01/01/2017
End date:31/12/2021

AMGEN Clinical Research Support

Project leader:José María Ribera
Code:Curs AMGEN ALL
Funding:
Start date:01/01/2018
End date:31/12/2018

Apoyo científico / Docente Solicitud de ayuda a la investigacion en leucemia aguda linfoblastica

Project leader:José María Ribera
Code:AMG169
Funding:
Start date:01/01/2017
End date:31/12/2018

Estudi observacional prospectiu de tractament adaptat al risc de la LMA i les SMD a Catalunya

Project leader:José María Ribera
Code:SLT002/16/00433
Funding:
Start date:01/04/2017
End date:31/12/2019

Previous projects

Study of the frequency and prognostic significance of Copy Number Alterations and CpG island methylation status in adult B-precursor Acute Lymphoblastic Leukemia patients enrolled in risk-adapted protocols of the Spanish PETHEMA Group

Project leader:José María Ribera
Code:RD12/0036/0829
Funding:
Start date:01/01/2011
End date:30/06/2014

Grup de Recerca Emergent: Grup de Recerca d'estudi de les neoplàsies hematològiques del IJC-Campus Trias i Pujol

Project leader:Francesc Solé
Code:2014SGR225
Funding:
Start date:01/01/2015
End date:31/12/2017