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

Abstract

34Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains 35 heavily based on phenotypic resemblance to normal hematopoietic precursors. This 36 framework can provide diagnostic challenges for immunophenotypically heterogeneous 37 immature leukemias, and ignores recent advances in understanding of developmental 38 multipotency of diverse normal hematopoietic progenitor populations that are 39 identified by transcriptional signatures. We performed transcriptional analyses of a 40 large series of acute myeloid and lymphoid leukemias and detected significant overlap 41 in gene expression between cases in different diagnostic categories. Bioinformatic 42 classification of leukemias along a continuum of hematopoietic differentiation identified 43 leukemias at the myeloid/T-lymphoid interface, which shared gene expression 44 programs with a series of multi or oligopotent hematopoietic progenitor populations, 45 including the most immature CD34+CD1a-CD7-subset of early thymic precursors. 46Within these interface acute leukemias (IALs), transcriptional resemblance to early 47 lymphoid progenitor populations and biphenotypic leukemias was more evident in 48 cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses 49 revealed that expression of IAL transcriptional programs significantly correlated with 50 poor outcome in independent AML patient cohorts. Our results suggest that traditional 51 binary approaches to acute leukemia categorization are reductive, and that 52 identification of IALs could allow better treatment allocation and evaluation of 53 therapeutic options.54 55 3 Introduction: 56 Successful management of acute leukemia is underpinned by accurate diagnostic 57 classification, which provides a basis for treatment allocation, risk stratification and 58 implementation of targeted therapies (1). Although knowledge of the molecular 59 landscape of leukemia has increased enormously over the past decades, contemporary 60 classification remains heavily predicated on simple immunophenotypic resemblance to 61 either myeloid or lymphoid normal hematopoietic precursors (2). While this system has 62 historically been successful, some leukemia categories provide specific diagnostic and 63 therapeutic challenges. The current World Health Organization (WHO) classification (2) 64 recognizes acute leukemias of ambiguous lineage that either lack lineage-specific 65 markers (acute undifferentiated leukemias, AUL) or express a mixture of myeloid and 66 lymphoid antigens (mixed phenotype acute leukemias, MPAL). There is little consensus 67 on the best treatment approaches for these patients, and prognosis is usually poor (3-68 5). 69 This framework also poses difficulties for some cases of T-acute lymphoblastic leukemia 70 (T-ALL) and acute myeloid leukemia (AML). T-ALL can be subclassified by 71 immunogenotypic and phenotypic resemblance to either immature/ early thymic 72 precursor (ETP), early cortical or late cortical normal T-progenitor equivalents (6, 7). 73 However, ...