Research group on Stem cell biology, developmental leukemia, and immunotherapy, guided by Pablo Menéndez, is studying the developmental origin and the genetic and epigenetic making of B-cell Acute Lymphoblastic Leukemia (B-ALL) in children younger than 1-year-old (infants), in the frame of the ERC-EU project INFANTLEUKEMIA (GA 64903). Menéndez and his team have a particular interest in those patients harboring Mixed Lineage Leukemia gene (MLL) rearrangements (chromosomal translocations), which have been shown to arise prenatally.

Infant leukemia with MLL rearrangements still represents an outlier and is associated with unfavorable outcomes. The mutational landscape of infant B-ALL is the most silent among all the cancers sequenced to date. Among the patients harboring the translocation t(4;11)+, those who express the reciprocal derivative known as AF4-MLL are associated with a much better clinical outcome.

Pablo Menéndez and his group have investigated what is the most common genomic landscape to define a better or worse prognostic. The main achievements so far reached with the work of this project have been the detection of relevant associations of MLL with other genes. Studies in primary samples and disease models have revealed that the expression of the reciprocal derivative AF4-MLL underlies the HOX gene signature observed in t(4;11)+ leukemias. The only recurrent secondary mutations in infant B-ALL are found in K/N-Ras and have no clinical impact but is associated with the infiltration of the Central Nervous System (CNS).

Additionally, the antigen NG2 is specific for MLL-rearranged leukemias, plays a crucial role in leukemic cell migration, and enriches for CNS-infiltrating cells. Targeting NG2 represents a promising therapeutic approach when combined with standard induction chemotherapy, as blockage of NG2 induces the exit of leukemic blasts to peripheral blood, where they become more vulnerable to chemotherapy.

In another stage of this project, integrative whole-genome methylome-transcriptome studies on a large cohort of patients revealed cancer cell vulnerabilities in MLL-rearranged infant B-ALL. Until the end of 2020, Menéndez Lab will complete the analysis of the methylome data, and perform the functional target validation.