Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles

Abstract

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-Down syndrome (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression, and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only two NDS cases (3.1%) (Fisher’s exact p = 0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters, and enrichment of highly methylated genes for specific pathways and transcription factor binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

“…2A), and were not associated with CRLF2 status. This finding is consistent with previous genomic studies in DS-ALL (27,28), and to our knowledge, has not been reported in other cancers, including leukemias.…”

High modal number and triple trisomies are highly correlated favorable factors in childhood B-cell precursor high hyperdiploid acute lymphoblastic leukemia treated according to the NOPHO ALL 1992/2000 protocols

“…The former frequency is similar to the one described by Heerema et al, 4 whereas the latter is lower than the 5-16% previously reported in DS-ALL. [26][27][28][29][30] Both DS patients in our series are alive in first complete remission more than 9 years after diagnosis. Thus, our data neither support a notable prevalence of DS in HeH patients nor indicate a particularly poor outcome of DSHeH cases.…”

Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

“…25 Although these genes have not been reported to be deleted in ALL or otherwise associated with this disease, the observed 6p imbalances overlap to some extent with 6p deletions reported in Down syndrome-associated ALL and other histone clusters on 6p have been shown be deleted in pediatric ALL, with methylation arrays suggesting that histone deletions are associated with methylation alterations. 26,27 Thus, HIST1H2BD and HIST1H1E may be added to the growing list of acute leukemia-associated genes, for example DNMT3, EZH2, HOX family, and MLL, that 13 contribute to the leukemogenic process through deregulated CpG methylation or histone modification. [28][29][30][31] Among the other recurrent gene targets, most -CDKN2A, EBF1, ETV6, IKZF1, PAX5, RAG1, and TBL1XR1 -have been thoroughly discussed previously.…”