Clinical and genomic characterization of patients diagnosed with the provisional entity acute myeloid leukemia with BCR‐ABL1, a Swedish population‐based study

Abstract

Acute myeloid leukemia (AML) with t(9;22)(q34;q11), also known as AML with BCR‐ABL1, is a rare, provisional entity in the WHO 2016 classification and is considered a high‐risk disease according to the European LeukemiaNet 2017 risk stratification. We here present a retrospective, population‐based study of this disease entity from the Swedish Acute Leukemia Registry. By strict clinical inclusion criteria we aimed to identify genetic markers further distinguishing AML with t(9;22) as a separate entity. Twenty‐five patients were identified and next‐generation sequencing using a 54‐gene panel was performed in 21 cases. Interestingly, no mutations were found in NPM1, FLT3, or DNMT3A, three frequently mutated genes in AML. Instead, RUNX1 was the most commonly mutated gene, with aberrations present in 38% of the cases compared to around 10% in de novo AML. Additional mutations were identified in genes involved in RNA splicing (SRSF2, SF3B1) and chromatin regulation (ASXL1, STAG2, BCOR, BCORL1). Less frequently, mutations were found in IDH2, NRAS, TET2, and TP53. The mutational landscape exhibited a similar pattern as recently described in patients with chronic myeloid leukemia (CML) in myeloid blast crisis (BC). Despite the concomitant presence of BCR‐ABL1 and RUNX1 mutations in our cohort, both features of high‐risk AML, the RUNX1‐mutated cases showed a superior overall survival compared to RUNX1 wildtype cases. Our results suggest that the molecular characteristics of AML with t(9;22)/BCR‐ABL1 and CML in myeloid BC are similar and do not support a distinction of the two disease entities based on their underlying molecular alterations.

Imatinib with intensive chemotherapy in AML with t(9;22)(q34.1;q11.2)/BCR::ABL1. A DATAML registry study.

“…Relapse-free and overall survival were better than in earlier studies that contributed to classify this entity as high-risk disease. 4,7,14 In a retrospective study from Korea on 29 patients with Ph + AML including 7 with additional inv(16), the CR rate was 81.5% following imatinib added to intensive chemotherapy. 17 Two recent studies from transplantation registries showed a better outcome in de novo patients who received an allogeneic stem cell transplantation.…”

“…CML-BP are characterized by frequent splenomegaly, signi cant blood or marrow basophilia, additional chromosomal abnormalities (ACA), or ABL1 mutations. 3,5,7,8 AML with BCR::ABL1 is much less described but has been associated with a lower frequency of ACA and with a unique gene signature including deletion in IKZF1, CDKN2A and/or in the immunoglobulin and T cell receptor genes. 9 CD25 and ID4 mRNA expression might also differentiate AML with BCR::ABL1 from CML-BP.…”

A rare presentation of BCR‐ABL1 and RUNX1‐MECOM rearrangement in a pediatric patient with acute myeloid leukemia

“…AML with BCR::ABL1 fusion is considered as high‐risk with a poor prognosis that is dependent upon other coexisting genetic aberrations. The diagnosis of AML with BCR::ABL1 fusion requires more than 20% blasts expressing a myeloid immunophenotype in the bone marrow or peripheral blood 11 . and distinguishing AML with BCR::ABL1 from initial myeloid blast phase of CML can be challenging 12 .…”

“…The diagnosis of AML with BCR::ABL1 fusion requires more than 20% blasts expressing a myeloid immunophenotype in the bone marrow or peripheral blood. 11 and distinguishing AML with BCR::ABL1 from initial myeloid blast phase of CML can be challenging. 12 The patient showed more than 20% blasts expressing a myeloid immunophenotype in the bone marrow and peripheral blood, showed BCR::ABL1 at initial diagnosis, and lack of features of CML prior to or at diagnosis or after therapy.…”

Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies

“…These are proto-oncogenes and they fall into two categories: gain-of-function mutations in proto-oncogenes, which enhance cell growth and division; and loss-of-function mutations in tumor suppressor genes that inhibit unhindered cell growth and cell cycle checkpoint activation among other things ( 185 ). The loss of function mutations includes the p53 and retinoblastoma (Rb) protein ( 186 ) while the gain of function mutations include K-ras and Bcr-abl protein ( 187 ). The Rb family of proteins play a key role in the regulation of the cell cycle progression from the G1 to S phase.…”