2019 January 16

A new therapeutic target for a rare infant leukemia with poor prognostic

The group led by Pablo Menéndez publish research identifying a new therapeutic target for a rare infant leukemia with poor prognostic.

The Stem Cell Biology, Developmental Leukemia and Immunotherapy Group led by Pablo Menéndez at the Josep Carreras Leukaemia Research Institute have identified a new therapeutic target for a rare type of infant leukemia that has a very poor outcome.

Belén López-Millan and Clara Bueno, who are responsible for the study published in Leukemia (Nature Research) this month, explain that “most cases of infant leukemia are acute lymphoblastic leukemia type B.  This is the most frequent childhood cancer and usually has a good prognostic and a favourable outcome, more than 80% are cured.  However, there is a sub-type of leukemia called MLLr-B-ALL which normally has a very poor outcome indeed with devastating effects for the families of the patients, who do not usually respond to conventional therapies and relapse very quickly.  We desperately need a target which we can attack with a new medication to halt this disease,” they add.

Leukemic lymphoblasts express abnormal cellular markers on their exteriors, these can be detected by advanced flow cytometry techniques.  In this case, the lymphoblasts of acute lymphoblastic leukemia with alternations in the MLL gene express the antigen NG2 (neuron-glial antigen 2, also known as chondroitin sulphate proteoglycan-4).

The MLLr-B-ALL patients fail to respond to the standard treatments and leukemia cells move into the central nervous system.  In this case, doctors usually decide to undertake a bone marrow transplant from a family member or unrelated donor after they have achieved remission.  The big drawback is that it is extremely difficult to reach a state of remission.

In 2017 Pablo Menendez’s laboratory demonstrated that NG2 is involved in the capacity of the leukemia cells to invade other tissues in this type of leukemia.  To be exact, they demonstrated that the expression of NG2 defines those blasts (immature blood cells) able to colonize the central nervous system.  The cells remain hidden in the central nervous system and the proportion of cells there is greater than those identified in the clinical diagnosis.  Taking this finding into account López-Millan and Bueno started looking to block NG2 to increase the effectiveness of the treatment for this group of patients by using a monoclonal antibody or the enzyme condroitinase ABC, used in standard treatments of the patients.  The results are promising, studies on mice indicate a good response and few relapses with associated better survival rates.  Additionally, the use of the antigen to NG2 does not increase the toxicity of the treatment. The team has filed a patent for this approach.

Pablo Menéndez, responsible for the Josep Carreras Leukaemia Research Institute laboratory on its Campus Clínic-UB in Barcelona explains that “infant leukemia affects 400 children a year in Spain.  The rarest cases affect fewer than ten children. “It is essential that public institutions as well as private ones such as the Josep Carreras Foundation invest in research to find out more about these sub-types of the illness and find new treatments. 

Original Article

NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia

Belen Lopez-Millan, Diego Sanchéz-Martínez, Heleia Roca-Ho, Francisco Gutiérrez-Agüera, Oscar Molina, Rafael Diaz de la Guardia, Raúl Torres-Ruiz,2, Jose Luís Fuster, Paola Ballerini, Ute Suessbier, Cesar Nombela-Arrieta, Clara Bueno, Pablo Menéndez.  Leukemia (January 2019)

 

Funding Information

This work has been supported by the European Research Council (CoG-2014-646903 and PoC-2018-811220), the Spanish Ministry of Economy-Competitiveness (SAF2016), and the Catalan Government (SGR330 and PERIS 2017) to PM, and the Asociación Española Contra el Cáncer (AECC), Beca FERO, and the ISCIII/FEDER (PI17/01028) to CB RT-R, and OM are supported by postdoctoral fellowships from the AECC scientific foundation and the Catalan Government (Beatriu de Pinos, BP00048), respectively. PM also acknowledges the financial support from the Obra Social La Caixa-Fundaciò Josep Carreras and “Premio Miguelín”. PM is investigator of the Spanish Cell Therapy cooperative network (TERCEL).