Distinct clinical characteristics ofDUX4-andPAX5-altered childhood B-lymphoblastic leukemia

Abstract

In childhood B-ALL, among the recently described subtypes were DUX4 and PAX5 altered (PAX5alt). Using whole transcriptome RNA sequencing (RNA-Seq) in 377 B-ALL children from MaSpore ALL 2003/2010 (MS2003/MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n= 51; 14%) and PAX5alt (n= 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor Day 33 MRD (n=12/44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse (CIR) 8.9% [95% CI, 2.8% to 19.5%], 5-year OS 97.8% [95% CI, 85.3% to 99.7%]). In MS2003, 21% DUX4 B-ALL had poor peripheral blood (PB) response to prednisolone at day 8, higher than other subtypes (8%; P=0.03). In MS2010, with vincristine at day 1, no day 8 poor PB response was observed in DUX4 subtype (P=0.03). PAX5alt group had an intermediate risk of relapse (5-year CIR 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared to MS2003, outcome of PAX5alt B-ALL with IKZF1 co-deletion was improved by treatment intensification in MS2010 (5-year CIR 80.0% vs 0%; P=0.05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 co-deletion.

Epigenetic activation of the FLT3 gene by ZNF384 fusion confers a therapeutic susceptibility in acute lymphoblastic leukemia

“…1c), again with consistent activation across ZNF384 fusions (Fig. 1d) 25 . FLT3 mutation was uncommon in ZNF384-rearranged ALL, identified in 5 of 66 cases (7.6%) from these two cohorts (Fig.…”

Prognostic significance of copy number variation in B-cell acute lymphoblastic leukemia

“…In pediatric B-ALL groups, the prognosis of PAX5 deletion was strongly dependent on IKZF1 codeletion ( 61 , 80 ). However, no significant prognostic correlation was observed in PAX5 deletions alone in children ( 74 ).…”

N‐terminus DUX4‐immunohistochemistry is a reliable methodology for the diagnosis of DUX4‐fused B‐lymphoblastic leukemia/lymphoma (N‐terminus DUX4 IHC for DUX4‐fused B‐ALL)

“…Additional studies have worked to characterize further the landscape of B‐ALLs by their distinctive gene expression patterns and mutational profiles, with discovery of novel translocations and gene mutations driving pathophysiology and leukemogenesis 4–9 . Harvey et al, 9 in a study of gene expression profiles of cases of clinically defined high‐risk B‐ALLs, elucidated clinicopathologic and molecular features of a cohort of 21 cases (“cluster 6”) exhibiting high expression of outlier genes AGAP1 , CCNJ , CHST2/7 , CLEC12A/B , PCDH17 , and PTPRM , frequent ETS transcription factor gene ERG deletions, and extremely favorable clinical outcomes, even in the context of otherwise unfavorable gene mutations, including IZKF1 mutations, 9 and end‐induction minimal residual disease 10 . Several groups have further shown the molecular mechanisms driving this subtype of B‐ALL to be tied to the sequential dysregulation of the double homeobox 4 ( DUX4 ) and ERG genes.…”

“…[4][5][6][7][8][9] Harvey et al, 9 in a study of gene expression profiles of cases of clinically defined high-risk B-ALLs, elucidated clinicopathologic and molecular features of a cohort of 21 cases ("cluster 6") exhibiting high expression of outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, PCDH17, and PTPRM, frequent ETS transcription factor gene ERG deletions, and extremely favorable clinical outcomes, even in the context of otherwise unfavorable gene mutations, including IZKF1 mutations, 9 and end-induction minimal residual disease. 10 Several groups have further shown the molecular mechanisms driving this subtype of B-ALL to be tied to the sequential dysregulation of the double homeobox 4 (DUX4) and ERG genes. B-ALLs with DUX4 translocation are reported to constitute approximately 5% of pediatric B-ALLs, 11,12 and have been show to exhibit a particular predilection for B-ALLs occurring in adolescents and young adults, constituting an estimated 15% of these cases.…”