The acute lymphoblastic leukemia of Down Syndrome - Genetics and pathogenesis

Area of Science:

• Pediatric Oncology
• Genetics
• Immunology

Background:

• Children with Down syndrome (DS) exhibit a significantly elevated risk for acute lymphoblastic leukemia (ALL), predominantly of the B-cell precursor (BCP) type.
• T-cell acute lymphoblastic leukemia (T-ALL) and infant leukemia are rare in this population.

Purpose of the Study:

• To investigate the heterogeneity of Down syndrome acute lymphoblastic leukemia (DS-ALL).
• To identify genetic alterations and molecular pathways involved in DS-ALL.
• To explore potential targeted therapeutic strategies for DS-ALL.

Main Methods:

• Gene expression profiling
• Cytogenetic analysis
• Genomic rearrangement analysis
• Mutation analysis of receptor and JAK-STAT pathway components

Main Results:

• DS-ALL is a heterogeneous disease.
• Over half of DS-ALL cases show aberrant expression of the thymic stromal lymphopoietin (TSLP) receptor CRLF2 due to genomic rearrangements.
• These rearrangements frequently co-occur with activating mutations in CRLF2 or JAK-STAT pathway components.
• JAK-STAT pathway activation was observed, suggesting therapeutic targets.

Conclusions:

• The aberrant expression of CRLF2 and JAK-STAT pathway activation are key features of a subset of DS-ALL.
• Targeted inhibition of the JAK-STAT pathway presents a promising therapeutic avenue for children with DS-ALL.
• The underlying reasons for the increased risk of BCP-ALL and CRLF2 aberrations in DS, and the specific genes on trisomic chromosome 21 involved, remain to be elucidated.