A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis

Abstract

Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a−CD7− subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.

PHF6 Mutations in Hematologic Malignancies

“…Bond et al. performed an analysis of the transcriptional program of AMLs and T-ALLs and identified an expression program at the interface of these two diseases ( 73 ). Comparing T-ALL to T-ALL-like AMLs and AML-like T-ALLs, it was found that all T-ALLs with PHF6 mutations were accompanied by NOTCH1 mutations, whereas 3/5 PHF6 mutated interface cases lacked NOTCH1 mutations ( 73 ).…”

MEF2C opposes Notch in lymphoid lineage decision and drives leukemia in the thymus

“…This mouse model mirrors patients with ETP-ALL who can express both T and B markers, also referred to as T/B MPAL ( 55 , 56 ). MPAL is defined by coexpression of 2 or 3 myeloid, T, and/or B cell lineage markers and likely arises from uncommitted hematopoietic progenitors ( 57 , 71 ). T/B MPAL is particularly rare but originates from uncommitted ETP cells and could be considered as the earliest subset of ETP-ALL.…”

Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies

“…They showed that more than 15% of leukemia cases could not be reliably classified into either AML or T-ALL and they defined these cases “AML-like T-ALL” and the category was associated with poor prognosis. It is important to note that not all cases of AML-like T-ALL show immature immunophenotype or ETP-ALL phenotype as defined by immunophenotypic criteria ( 20 ). Furthermore, single-cell RNA sequencing has demonstrated the expression of signature genes with a spectrum of hematopoietic cells (e.g., mature thymocytes, hemopoietic stem cell, multipotent progenitors, and granulocytic-macrophage progenitors) within the same ETP-ALL cell ( 21 ).…”