![]() These clusters were replicated in the second cohort of 40 patients (Supplementary Figs. ![]() Non-negative matrix factorization (NMF) followed by consensus clustering uncovered three distinct transcriptomic clusters, initially labeled C1, C2 and C3 (Fig. The first cohort of 57 samples from 53 patients (Supplementary Table 1 46 de novo BCR-ABL1 B-cell acute lymphoblastic leukemia (B-ALL), 5 CML in lymphoid blast crisis and 2 mixed phenotype acute leukemia (MPAL)) was purified for blasts and subjected to RNA sequencing (RNA-seq Extended Data Fig. Two patient cohorts spanning 20 years (1992–2019) with clinical follow-up data were collected (Extended Data Fig. Our data propose a model of pathogenesis that explains the molecular and clinical heterogeneities observed in this disease.ĭistinct transcriptomic clusters of BCR-ABL1 lymphoblastic leukemia To address the issues raised above, we collected a cohort of BCR-ABL1 lymphoblastic leukemia patient samples with extensive treatment response data. The origins of these disease phenotypes and how they influence treatment outcomes are not well understood 7. However, recent work tracking residual disease in patients shows that p190 isoform can be sustained in HSC but can produce acute leukemia with a typical B-cell phenotype. Rationally, this leads to the notion that mixed-lineage phenotype is related to the p210 isoform originating in an HSC, whereas the classic B-cell phenotype is related to the p190 isoform originating in a committed B-cell progenitor. ![]() The long isoform (p210) has been shown to originate in a hematopoietic stem cell (HSC), whereas the short isoform (p190) has been shown to originate in a B-cell progenitor 6. There are two major isoforms of BCR-ABL1. These phenotypes are thought to reflect the differentiation potential of the cell-of-origin, but this remains controversial. Furthermore, this disease presents two drastically different molecular phenotypes-mixed-lineage and classic B-cell precursor. The co-occurrence of multiple driver alterations makes it difficult to decipher their roles in the heterogeneity of treatment outcomes among patients. Genetic alterations in other B-cell differentiation genes, such as PAX5, CDKN2A/B and EBF1, are also frequent in this disease 4. As many patients with BCR-ABL1 lymphoblastic leukemia demonstrate durable responses to treatment, some of them must harbor IKZF1 losses given the high frequency of this alteration. Loss of IKZF1 is present in 80% of patients 4 and mouse models have shown that IKZF1 alterations are linked to TKI resistance 5. The genomics of BCR-ABL1 lymphoblastic leukemia is well described. TKI resistance is mostly viewed through the lens of kinase domain mutations, but whether kinase domain-independent mechanisms of therapy resistance contribute to the emergence of kinase domain-mutant clones is unknown. Most patients relapse due to the emergence of clones with kinase domain mutations, but 30–40% of patients relapse without kinase domain mutations, which is poorly understood 3. Approximately half of the patients diagnosed with BCR-ABL1 lymphoblastic leukemia die within 5 years of being diagnosed 2. Most CML patients can expect to live a near-normal lifespan owing to targeted therapy with tyrosine kinase inhibitors (TKIs), whereas the survival of BCR-ABL1 lymphoblastic leukemia patients remains dismal despite TKI intervention 1, 2. Despite sharing the same initiating event, patients with these diseases show vastly different outcomes. The BCR-ABL1 fusion drives two hematopoietic malignancies-chronic myelogenous leukemia (CML), a myeloproliferative disorder, and BCR-ABL1 lymphoblastic leukemia, an acute leukemia mostly of the B-cell lineage. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms. Interestingly, these events were absent in BCR-ABL1 + preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. Through deep molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood.
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