Paired Analyses of Diagnostic and Relapse Samples of MLL rearranged Infant Acute Lymphoblastic Leukemia Reveals Potential Therapy-Resistant Genomic Alterations

Infant acute lymphoblastic leukemia (ALL) (less than one-year-old) is a rare, aggressive disease, with unique biological and clinical features. It is associated with 11q23 MLL rearrangements (MLL-R), and a high relapse risk. In contrast, in childhood ALL (age 1-18 years) the majority survives beyond 5 years, and only 15-20% of patients relapse. The genomic landscape in the latter group has been investigated quite extensively, and is has proven to be of diagnostic and prognostic significance. Paired diagnostic and relapse samples have identified frequent microdeletions in B-cell differentiation and cell cycle regulating genes IKZF1, EBF1 and CDKN2A/B. Alterations in these genes, either at diagnosis or relapse are linked to therapy-resistance. In contrast, data on copy-number alterations in infant ALL, particularly at relapse, are very limited. Therefore, we investigated two infant ALL at diagnosis and relapse by molecular cytogenetic analyses including high-density SNP array.

A six-months-old boy was diagnosed with pro B-ALL. Molecular cytogenetic analyses revealed a t(4;11) MLL-AFF1 positive karyotype. SNP array resulted in a balanced profile. After a MUD-SCT the ALL relapsed at age 1.1-years. Cytogenetics demonstrated the t(4;11) stemline, and evolution with two related sidelines, one with a dic(1;19) and another with an unbalanced t(1;18), both resulting in 1q gain. In addition, SNP array analysis revealed homozygous loss of 7p12.2 IKZF1 due to an overlapping and an intragenic exon 2-3 deletion.

The second case, a 3-months-old boy with pre B-ALL, showed a complex t(11;19) MLL-MLLT1 positive karyotype. Microarray analysis resulted in a balanced profile. At age one-year the ALL relapsed after a sibling-SCT, with the complex karyotype. SNP array showed a chimeric profile with only two small heterozygous 19p13.3 deletions, one including TCF3.

In childhood ALL drug resistant blasts at relapse are probably subclonal at diagnosis, or develop during therapy, with frequent microdeletions of B-cell differentiation regulating genes IKZF1 and EBF1. These alterations are found particularly in MLL-wt ALL, whereas MLL-R ALL is associated with epigenetic perturbations. Interestingly, in our two cases of infant MLL-R ALL we observe, at relapse only, microdeletions of B-cell differentiation regulating genes IKZF1 and TCF3. It is of importance to study more paired cases to further define the mutational landscape of this unique, but ill-fated subtype of ALL.