2019 February 12

The Josep Carreras Leukaemia Research Institute and the University of Cantabria lead a pioneering European study on one of the most lethal forms of childhood leukaemia

New studies show that the genome for acute lymphoblastic leukemia pro B with t translocation (4; 11) (MLL-AF4 +) is more stable than other forms.  The Stem Cell Biology, Developmental Leukemia and Immunotherapy Group led by Pablo Menéndez in collaboration with researchers from the Univesity of Cantabria have also discovered a biomarker that will be a valuable indicator of the prognostic for patients with this type of leukemia.

The Stem Cell Biology, Developmental Leukemia and Immunotherapy Group, of the Clinic-UB Campus of the Josep Carreras Leukaemia Research Institute (IJC), led by Dr Pablo Menéndez, ICREA Research Professor has published two papers in Haematogica, both carried out in collaboration with Dr Ignacio Varela of the University of Cantabria this February. The studies present a new focus and new prognostic tools to improve the survival rate for one of the most lethal forms of childhood leukemia.

Acute lymphoblastic leukemia Type B is the most frequent childhood cancer (a third of paediatric neoplasms) and it usually has a good prognostic with over 85% of cases being cured. However, there are sub-types of the disease with poorer outcomes including acute lymphoblastic leukemia pro B with t translocation (4; 11) (MLL-AF4 +) in new-borns (under 1 year), which is nearly always fatal. This type of leukemia, which originates in the embryo usually means the disease spreading to the nervous system, which is what makes it so difficult to cure.

In one part of the study the researchers have sequenced the genomes of 124 children diagnosed with this sub-type of leukemia.  It is one of the widest studies ever undertaken up to now on leukemia in new-borns and has been possible due to the collection of samples from European patients treated under the Interfan Protocol at the Trousseau Hospital in Paris, France; the Princess Maxima Centre for Paediatric Oncology in Utrecht and the Erasmus University in Amsterdam, both in Holland and the Monza Paediatric Hospital in Italy.

The study has revealed that the genome for this type of leukemia is the most stable of any childhood cancer studied up to now. “The question that we need to resolve is why does a cancer with such a stable genome behave so aggressively?” Menendez tells us. This research suggests that there may be epigenetic changes that are acquired before birth and the group has also detected an important biomarker for prognostics for this type of the disease. In some patients the gene AF4-MLL is expressed and they have a much higher probability of survival (62.4% as opposed to 11.7%).  This finding will be important when choosing the most intensive and most effective treatments for each individual patient.

A second branch of the research, also published in Haematologica, has been led by Dr Clara Bueno from the same group at the IJC, and it concentrates on the same type of leukemia, but focusses on the type of embryonic cell in which the mutation occurs.  “We are asking what factors come together for leukemia to appear on the embryo?” Bueno explains.

The t translocation in chromosome (4; 11) is associated with high risk acute infant lymphoblastic leukemia pro-B and occurs during embryonic haematopoiesis; the process in which elements of the blood of the embryo are formed, mature and develop.  In the embryo haematopoiesis has three phases: first in the aorta, during the first weeks; then in the liver, between weeks 18-20 of pregnancy and later in the bone marrow, where it continues after birth.  The group have seen that when the translocation occurs and there is a fusion of MLL-AF4 (MA4) and AF4-MLL (A4M) there is a molecular and functional effect which alters normal haematopoiesis, a process in which these genes are involved.

Bueno’s team also carried out an epigenetic study to see what changes not involving the DNA are occurring in the genes of the embryo to understand more about the mechanisms that have such a devastating effect in this disease.

 Funding Information

The group led by Dr Pablo Menéndez, ICREA Research Professor, is one of the few in the world that study this type of leukemia. To carry out this work Dr Menéndez has been financed by the European Research Council (CoG-2014-646903 and PoC-2018-811220), the Government of Catalonia (SGR330 and PERIS 2017-2019) the Spanish Ministry of Economy and Competitiveness    (SAF2016-80481-R and SAF2016-76758-R.  he also receives support from the Deutsche  José   Carreras   Leukämie  Stiftung financial  support from “la Caixa” Foundation, the Inocente Inocente Foundation,  the Ramon Areces Foundation and the Josep Carreras Foundation. He is a research member of the Spanish Cell Therapy cooperative Network (TERCEL). 

Clara Bueno is funded by the Spanish Association against cancer (AECC-CI-2015), the FERO Foundation and the Health Institute Carlos III (ISCIII/FEDER, PI17/01028 and  PI17/01028).

 

Reference Articles:

Unravelling the cellular origin and clinical prognostic markers of infant B-cell acute lymphoblastic leukemia using genome-wide analysis.  Agraz-Doblas, Bueno C, Bashford-Rogers R, Roy A, Schneider P, Bardini M, Ballerini P, Cazzaniga G, Moreno T, Revilla C, Gut M, Valsecchi MG, Roberts I, Pieters R, De Lorenzo P, Varela , Menendez P, Stam RW.

Haematologica. 2019 Jan 24. pii: haematol.2018.206375. doi: 10.3324/haematol.2018.206375. [Epub ahead of print]

 

Enhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusionsBueno C, Calero-Nieto FJ, Wang X, Valdés-Mas R, Gutiérrez-Agüera F, Roca-Ho H, Ayllon V, Real PJ, Arambile D, Espinosa L, Torres-Ruiz R7 Agraz-Doblas A8 Varela I9 de Boer J Bigas A, Gottgens B, Marschalek R, Menendez P.  Haematologica 2019 Jan 24. pii: haematol.2018.202044. doi: 10.3324/haematol.2018.202044. [Epub ahead of print]