Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia

Abstract

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co‐expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T‐lymphoid/myeloid MPAL (T/My MPAL‐NOS), 42 with Ph+ MPAL, 36 with B‐lymphoid/myeloid MPAL (B/My MPAL‐NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL‐NOS was similar to B/T MPAL‐NOS but differed from Ph+ MPAL and B/My MPAL‐NOS. T/My MPAL‐NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL‐NOS showed higher NOTCH1 mutations. By integrating next‐generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1–G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement‐like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement‐like characteristics. Subsequently, we analyzed single‐cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease‐like and common myeloid progenitor disease‐like signatures, G5 and G6 had high expression of granulocyte‐monocyte progenitor disease‐like and monocyte disease‐like signatures, and G7 and G8 had common lymphoid progenitor disease‐like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.

Genomic heterogeneity within B/T mixed phenotype acute leukemia in a context of an immunophenotype

“…Our study confirms previously characterized clinicopathological and molecular features of B/T MPAL, such as commonly occurring in adolescents and young adults (a median age of 19 years in our study) with a male predominance (3/3 males in our study), frequent involvement of PB/BM and extramedullary organs/lymph nodes (3/3 in our study), cytogenetic abnormalities (70–80%, 2/3 in our study) with a subset harboring complex karyotype (20–40%, 1/3 in our study), and recurrent genetic aberrations commonly present in T-ALL (2/3 in ours) [ [7] , [8] , [9] , [10] , [11] , 13 ].…”

“…Of MPAL subtypes, B/T MPAL with the blast population co-expressing both B- and T-cell lineage defining markers is exceedingly rare and accounts for ∼3% of MPAL [6] , [7] , [8] , [9] . Only ∼30 cases have been reported in the literature with comprehensive clinicopathological and molecular characterization [7] , [8] , [9] , [10] , [11] . B/T MPAL typically occurs in children, adolescents, and young adults with a male predominance.…”

Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity

“…A recent study applied a similar approach to transcriptomes of a large cohort of so-called MPAL patients and identified 8 distinct clusters with immunophenotype and genotype correlation. 16 G1-G4 with T/M phenotype and G5-G8 with B/M phenotype. Interestingly, G2 and G3 were enriched for NOTCH1 mutations but G2 had DNMT3A and G3 had PHF6 mutations, two molecular subsets initially reported by our group.…”

“…Genetically, MPAL often harbor fusions involving BCR::ABL1, KMT2A, ZNF384, BCL11B and PICAML::MLLT10, 12 and mutations in PHF6, DNMT3A, NOTCH1 and WT1. [13][14][15][16][17] In contrast, AML-MRC is enriched for MDS-defining cytogenetic abnormalities and so-called "MR" gene mutations (i.e., SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 with or without RUNX1). 18,19 TP53 mutations and monosomal/complex karyotypes are frequent in t-AML.…”

Extracellular matrix protein 1 (ECM1) is a potential biomarker in B-cell acute lymphoblastic leukemia

“…The best known is Ph-like ALL, which copies the signature of ones with BCR::ABL1 9 . Recently, more and more phenocopies were identi ed, including ETV6::RUNX1-like, KMT2A rearrangement-like, hyperdiploid like and so on 4,10,11 . These ndings improve the strati cation of B-cell ALL and offer potential treatment strategies for these newly de ned subgroups.…”