B-Lymphoblastic Leukemia/Lymphoma (BLL)

Overview

B-Lymphoblastic Leukemia/Lymphoma (BLL) is an aggressive hematologic malignancy of B-cell precursors. In OncoTree, BLL encompasses both B-ALL (acute lymphoblastic leukemia) and its lymphomatous counterpart. Hypodiploid ALL — including near haploid (24–31 chromosomes) and low hypodiploid (32–39 chromosomes) subtypes — represents a high-risk BLL subgroup with distinct genomic profiles.

Cohorts in the corpus

  • all_stjude_2013: 124 pediatric hypodiploid ALL cases (50 near haploid, 26 low hypodiploid, and others) plus 117 adult ALL cases; WGS/WES with SNP array profiling.

Recurrent alterations

  • Near haploid ALL (24–31 chromosomes): RTK/Ras pathway alterations in 70.6% of cases, including NF1 (44.1%), NRAS, KRAS, FLT3, PTPN11, and MAPK1 mutations; IKZF3 deletions in 13.2%; CREBBP alterations in 32% PMID:23334668.
  • Low hypodiploid ALL (32–39 chromosomes): TP53 alterations in 91.2% of pediatric cases (43.3% inherited, linked to Li-Fraumeni syndrome); IKZF2 deletions in 52.9%; RB1 alterations in 41.2% PMID:23334668.
  • Both subtypes show activation of Ras and PI3K signaling (elevated pERK, pmTOR, pS6) PMID:23334668.
  • DUX4/ERG B-ALL subtype identified in 141/1913 (7.6%) B-progenitor ALL cases (St. Jude/COG multi-center cohort); defined by IGH-DUX4 rearrangement (100%) and focal RAG-mediated ERG deletions (55.6%); expresses dominant-negative ERGalt isoform; associated with favorable outcome despite IKZF1 alterations in 36.7% of cases; transcriptome or genome sequencing required for reliable detection PMID:27776115.
  • PIPseq cohort identified BCR-ABL1-like RNA-seq signature leading to NUP214-ABL1 fusion detection in a relapsed BLL patient (addition of dasatinib produced deep remission enabling curative bone-marrow transplant); also FOXP1-ABL1, SMARCC2-PDGFRB, JAK1 K1026E, STAT5B I704L, and NT5C2 D407Y pharmacogenomic variant conferring nucleoside-analog resistance PMID:28007021

Subtypes

  • Near haploid ALL (24–31 chromosomes): RTK/Ras-driven; NF1 intragenic deletion (exons 15–35) is a hallmark.
  • Low hypodiploid ALL (32–39 chromosomes): TP53/RB1-driven; strongly associated with Li-Fraumeni syndrome in pediatric patients.
  • Masked hypodiploid ALL: hypodiploid genome masked by doubling; shares molecular features with underlying hypodiploid subtype.

Therapeutic landscape

  • PI3K inhibitor gdc-0941 and dual PI3K/mTOR inhibitor bez235 substantially inhibited proliferation in both near haploid and low hypodiploid ALL ex vivo PMID:23334668.
  • MEK inhibition alone was ineffective despite high Ras pathway mutation frequency; PI3K is the actionable downstream node PMID:23334668.

Sources

  • PMID:23334668 — Roberts et al., 2013, Nature Genetics: Genomic characterization of hypodiploid ALL.

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