Distinct outcomes, ABL1 mutation profile, and transcriptome features between p190 and p210 transcripts in adult Philadelphia-positive acute lymphoblastic leukemia in the TKI era

Abstract

Background The differential signaling and outcome of patients with p190 or p210 transcripts of BCR-ABL1 have been systematically investigated in chronic myeloid leukemia rather than in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Methods We analyzed the outcomes and ABL1 mutation profiles in 305 consecutive adult patients with Ph+ ALL treated with chemotherapy plus tyrosine kinase inhibitors. We also studied transcriptome features in two newly diagnosed patients with p190 and p210 using single-cell RNA sequencing (scRNA-seq). Results P190 and p210 were found in 199 (65%) and 106 (35%) patients, respectively. Compared to patients with p190, a higher white blood cell count (p = 0.05), platelet count (p = 0.047), BCR-ABL1 transcript level (p < 0.001), and lower bone marrow blasts (p = 0.003) were found in patients with p210. Patients with p210 had fewer types of ABL1 mutations (4 vs. 16) and a higher prevalence of T315I and E225K/V mutations (91.3% vs. 68.6%; p = 0.031). Patients with p210 had a similar complete remission rate (91.0% vs. 90.1%; p = 0.805) but a lower complete molecular remission rate at 1 month (9.9% vs. 22.0%; p = 0.031) compared with p190. Patients with p210 had lower 3-year overall survival (OS) and disease-free survival (DFS) rates than those with p190 (3-year DFS: 10.4% vs. 9.2%, p = 0.069, 3-year OS: 44.3% vs. 38.2%, p = 0.018, respectively). Multivariate analysis revealed that p210 was independently associated with worse OS [HR 1.692 (95% CI 1.009–2.838), p = 0.046]. Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) was associated with a better prognosis in patients with p210 (p < 0.0001). In addition, scRNA-seq data showed distinct molecular and cellular heterogeneity between bone marrow cells of the two transcripts. Conclusions Ph+ ALL patients with p190 and p210 had different clinical characteristics, outcomes, ABL1 mutation profiles, and transcriptome features. Allo-HSCT could improve the outcomes of patients with p210.

3D Amplified Single-Cell RNA and Protein Imaging Identifies Oncogenic Transcript Subtypes in B-Cell Acute Lymphoblastic Leukemia

“…B-ALL is a most common type of cancer in children, and cytogenetic classification is crucial for guiding therapeutic strategies, quantifying disease burden, and monitoring treatment responses . One of the important genetic alterations in B-ALL involves the translocation of chromosome 9, which includes the ABL1 gene, with chromosome 22, harboring the BCR gene, resulting in Philadelphia chromosome-positive (Ph+) B-ALL with extremely poor prognosis. , Indeed, Ph+ B-ALL patients exhibit distinct clinical characteristics and outcomes depending on the major (e13a2, e14a2) and minor (e1a2) breakpoint of the BCR-ABL1 fusion gene . Therefore, the prompt identification of the BCR-ABL1 gene fusion transcript is essential in B-ALL diagnosis and management to guide the treatment of tyrosine kinase inhibitor (TKI), which has greatly improved the outcome of Ph+ B-ALL .…”

“…30,31 Indeed, Ph+ B-ALL patients exhibit distinct clinical characteristics and outcomes depending on the major (e13a2, e14a2) and minor (e1a2) breakpoint of the BCR-ABL1 fusion gene. 31 Therefore, the prompt identification of the BCR-ABL1 gene fusion transcript is essential in B-ALL diagnosis and management to guide the treatment of tyrosine kinase inhibitor (TKI), which has greatly improved the outcome of Ph+ B-ALL. 30 However, karyotyping and BCR-ABL1 gene quantification often entail lengthy turnaround times in realworld clinical practice, thereby impeding the timely implementation of TKI treatment initiation and switching.…”

3D amplified single-cell RNA and protein imaging identifies oncogenic transcript subtypes in B cell acute lymphoblastic leukemia

“…B-ALL is a most common type of cancer in children, and cytogenetic classi cation is crucial for guiding therapeutic strategies, quantifying disease burden, and monitoring treatment responses 26 . One of the important genetic alteration in B-ALL involves the translocation of chromosome 9, which includes the ABL1 gene, with chromosome 22, harboring the BCR gene, resulting in Philadelphia chromosome-positive (Ph+) B-ALL with extremely poor prognosis 26,27 . Indeed, Ph + B-ALL patients exhibit distinct clinical characteristics and outcomes depending on the major (e13a2, e14a2) and minor (e1a2) breakpoint of the BCR-ABL1 fusion gene 27 .…”

“…One of the important genetic alteration in B-ALL involves the translocation of chromosome 9, which includes the ABL1 gene, with chromosome 22, harboring the BCR gene, resulting in Philadelphia chromosome-positive (Ph+) B-ALL with extremely poor prognosis 26,27 . Indeed, Ph + B-ALL patients exhibit distinct clinical characteristics and outcomes depending on the major (e13a2, e14a2) and minor (e1a2) breakpoint of the BCR-ABL1 fusion gene 27 . Therefore, the prompt identi cation of the BCR-ABL1 gene fusion transcript is essential in B-ALL diagnosis and management to guide the treatment of tyrosine kinase inhibitor (TKI), which has greatly improved the outcome of Ph + B-ALL 26 .…”