14q32 rearrangements deregulating BCL11B mark a distinct subgroup of T-lymphoid and myeloid immature acute leukemia.
Danika Di GiacomoRoberta La StarzaPaolo GorelloFabrizia PellaneraZeynep Kalender AtakKim De KeersmaeckerValentina PieriniChristine J HarrisonSilvia ArnianiMartina MorettiNicoletta TestoniGiovanna De SantisGiovanni RotiCaterina MatteucciRenato BassanPeter VandenbergheStein AertsJan CoolsBeat BornhauserJean-Pierre BourquinRocco Giovanni PiazzaCristina MecucciPublished in: Blood (2021)
Acute leukemias (ALs) of ambiguous lineage are a heterogeneous group of high-risk leukemias characterized by coexpression of myeloid and lymphoid markers. In this study, we identified a distinct subgroup of immature acute leukemias characterized by a broadly variable phenotype, covering acute myeloid leukemia (AML, M0 or M1), T/myeloid mixed-phenotype acute leukemia (T/M MPAL), and early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Rearrangements at 14q32/BCL11B are the cytogenetic hallmark of this entity. In our screening of 915 hematological malignancies, there were 202 AML and 333 T-cell acute lymphoblastic leukemias (T-ALL: 58, ETP; 178, non-ETP; 8, T/M MPAL; 89, not otherwise specified). We identified 20 cases of immature leukemias (4% of AML and 3.6% of T-ALL), harboring 4 types of 14q32/BCL11B translocations: t(2,14)(q22.3;q32) (n = 7), t(6;14)(q25.3;q32) (n = 9), t(7;14)(q21.2;q32) (n = 2), and t(8;14)(q24.2;q32) (n = 2). The t(2;14) produced a ZEB2-BCL11B fusion transcript, whereas the other 3 rearrangements displaced transcriptionally active enhancer sequences close to BCL11B without producing fusion genes. All translocations resulted in the activation of BCL11B, a regulator of T-cell differentiation associated with transcriptional corepressor complexes in mammalian cells. The expression of BCL11B behaved as a disease biomarker that was present at diagnosis, but not in remission. Deregulation of BCL11B co-occurred with variants at FLT3 and at epigenetic modulators, most frequently the DNMT3A, TET2, and/or WT1 genes. Transcriptome analysis identified a specific expression signature, with significant downregulation of BCL11B targets, and clearly separating BCL11B AL from AML, T-ALL, and ETP-ALL. Remarkably, an ex vivo drug-sensitivity profile identified a panel of compounds with effective antileukemic activity.
Keyphrases
- acute myeloid leukemia
- allogeneic hematopoietic stem cell transplantation
- acute lymphoblastic leukemia
- liver failure
- poor prognosis
- dna methylation
- gene expression
- intensive care unit
- drug induced
- hepatitis b virus
- small molecule
- immune response
- rheumatoid arthritis
- epithelial mesenchymal transition
- emergency department
- randomized controlled trial
- systemic lupus erythematosus
- cell proliferation
- oxidative stress
- aortic dissection
- acute respiratory distress syndrome
- double blind
- electronic health record
- genome wide identification
- genome wide analysis