Redefining the biological basis of lineage-ambiguous leukemia through genomics: BCL11B deregulation in acute leukemias of ambiguous lineage

Abstract

Acute leukemias of ambiguous lineage (ALAL), including mixed phenotype acute leukemia (MPAL) and related entities such as early T-cell precursor acute leukemia (ETP-ALL), remain diagnostic and clinical challenges due to limited understanding of pathogenesis, reliance of immunophenotyping to classify disease, and the lack of a rational approach to guide selection of appropriate therapy. Recent studies utilizing genomic sequencing and complementary approaches have provided key insights that are changing the way in which such leukemias are classified, and potentially, treated. Several recurrent genomic alterations define leukemias that straddle immunophenotypic entities, such as ZNF384-rearranged childhood B-ALL and B/myeloid MPAL, and BCL11B-rearranged T/myeloid MPAL, ETP-ALL and AML. In contrast, some cases of MPAL represent canonical ALL/AML entities exhibiting lineage aberrancy. For many cases of ALAL, experimental approaches indicate lineage aberrancy arises from acquisition of a founding genetic alteration into a hematopoietic stem or progenitor cell. Determination of optimal therapeutic approach requires genomic characterization of uniformly treated ALAL patients in prospective studies, but several approaches, including kinase inhibitors and BH3 mimetics may be efficacious in subsets of ALAL.

Keywords: 14q32; ALAL; BCL11B; Enhancer hijacking; Lineage ambiguous; Mixed phenotype acute leukemia.

Figure 1.. Gene expression profiling of acute leukemia reclassifies lineage ambiguous cases.

(A) tSNE analysis of 2,573 acute leukemia samples. All cases diagnosed as MPAL are shown according to MPAL subtype and/or known genomic alteration. The majority of B/myeloid MPAL cases cluster with B-ALL subtypes with shared genomic alteration. (B) tSNE analysis of all non-B-ALL cases. Two previously undescribed subgroups were identified, including cases with BCL11B SVs (circled in black) and cases with non-TCR LMO2 rearrangements (circled in orange). Figure reproduced from ref. [19].

Figure 2.. BCL11B SVs result in deregulated BCL11B expression through various enhancer-mediated mechanisms.

(A) Summary of patient-specific breakpoints organized by SV partner locus. Only breakpoints within the viewing region are shown and only for cases with an identifiable SV (6 cases excluded that lacked WGS). (B) H3K27ac HiChIP data for two patient samples showing enhancer hijacking by the ARID1B enhancer at the 6q25 locus (top) and de novo enhancer formation (BETA) resulting in BCL11B activation (bottom). The same genomic windows are shown for each sample to demonstrate that chromatin interactions between chromosome 14 and chromosome 6 are only observed in the case with the t(6;14) translocation (top). Magenta arrows show the breakpoint positions.

Figure 3.. Model of BCL11B-mediated lineage ambiguous leukemia guided by epigenetic analysis.

(A) representation of the two BCL11B alleles in normal and leukemic cells. In bone marrow HSCs/HSPCs (left panel), both alleles are actively repressed and the two T-lineage enhancers, ThymoD (which regulates BCL11B) and N-Me (which regulates MYC) are not active (dotted triangles), whereas the ARID1B enhancer with an unknown function is active (purple filled triangle). In normal T cell progenitors that have immigrated to the thymus (middle panel), BCL11B is expressed from both alleles, and the T lineage enhancers are active whereas the ARID1B enhancer no longer shows H3K27ac signal. In BCL11B-deregulated leukemia (right panel), BCL11B is only expressed from one allele, and the enhancer landscape reflects that of normal HSCs/HSPCs, suggesting BCL11B expression reflects an abnormal gene regulatory state. (B) Working model that depicts the mechanism of aberrant BCL11B expression. SVs result in enhancer hijacking (e.g. of the ARID1B enhancer depicted) or de novo enhancer formation (BETA). Together with constitutive FLT3 activation, either through mutation or upregulation, these genomic events drive development of a lineage ambiguous acute leukemia with stem, myeloid and T lineage features that result from a combination of the cell of origin (HSPC) and driving genomic lesion (BCL11B).