Acquisition of the Ph chromosome and BCR-ABL fusion product in AML-M2 and t(8;21) leukemia: cytogenetic and FISH evidence for a late event

Najfeld, Vesna; Geller, Matthew D.; Troy, Kevin; Scalise, Angela

doi:10.1038/sj.leu.2400974

Cited by 21 publications

(5 citation statements)

References 9 publications

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“…In 14 published cases, BCR-ABL was acquired upon AML relapse [11,55,[71][72][73][74][75][76][77]. In 7 of these 14 patients, the morphologic classification was given.…”

Section: ) Bcr-abl At Aml Relapsementioning

confidence: 99%

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features

et al. 2016

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BCR-ABL-positive acute myeloid leukemia (AML) is a rare subtype of AML that is now included as a provisional entity in the 2016 revised WHO classification of myeloid malignancies. Since a clear distinction between de novo BCR-ABL+ AML and chronic myeloid leukemia (CML) blast crisis is challenging in many cases, the existence of de novo BCR-ABL+ AML has been a matter of debate for a long time. However, there is increasing evidence suggesting that BCR-ABL+ AML is in fact a distinct subgroup of AML. In this study, we analyzed all published cases since 1975 as well as cases from our institution in order to present common clinical and molecular features of this rare disease. Our analysis shows that BCR-ABL predominantly occurs in AML-NOS, CBF leukemia, and AML with myelodysplasia-related changes. The most common BCR-ABL transcripts (p190 and p210) are nearly equally distributed. Based on the analysis of published data, we provide a clinical algorithm for the initial differential diagnosis of BCR-ABL+ AML. The prognosis of BCR-ABL+ AML seems to depend on the cytogenetic and/or molecular background rather than on BCR-ABL itself. A therapy with tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib is reasonable, but-due to a lack of systematic clinical data-their use cannot be routinely recommended in first-line therapy. Beyond first-line treatment of AML, the use of TKI remains an individual decision, both in combination with intensive chemotherapy and/or as a bridge to allogeneic stem cell transplantation. In each single case, potential benefits have to be weighed against potential risks.

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“…In 14 published cases, BCR-ABL was acquired upon AML relapse [11,55,[71][72][73][74][75][76][77]. In 7 of these 14 patients, the morphologic classification was given.…”

Section: ) Bcr-abl At Aml Relapsementioning

confidence: 99%

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features

et al. 2016

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“…In this context, secondary BCR::ABL1 fusion could act as a late cooperating event within the multi-step pathogenesis. It may also arise from de novo AML, in which CBFB::MYH11, GATA2::MECOM, KMT2A::AFDN, PML::RARA, or RUNX1::RUNX1T1 are rearranged at diagnosis [20][21][22][23][24][25][26][27]. Secondary BCR::ABL1 fusion has also been found to occur in AML after treatment with an FLT3 inhibitor [28,29].…”

Section: Discussionmentioning

confidence: 99%

Deciphering Potential Molecular Signatures to Differentiate Acute Myeloid Leukemia (AML) with BCR::ABL1 from Chronic Myeloid Leukemia (CML) in Blast Crisis

Boucher,

Sorel,

Desterke

et al. 2023

IJMS

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Acute myeloid leukemia (AML) with BCR::ABL1 has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity by integrating clonal architecture analysis, mutational landscape assessment, and gene expression profiling. We analyzed a large retrospective cohort study including CML and AML patients. Two AML patients harboring a BCR::ABL1 fusion were included in the study. We identified BCR::ABL1 fusion as a primary event in one patient and a secondary one in the other. AML-specific variants were identified in both. Real-time RT-PCR experiments demonstrated that CD25 mRNA is overexpressed in advanced-phase CML compared to AML. Unsupervised principal component analysis showed that AML harboring a BCR::ABL1 fusion was clustered within AML. An AML vs. myeloid BC-CML differential expression signature was highlighted, and while ID4 (inhibitor of DNA binding 4) mRNA appears undetectable in most myeloid BC-CML samples, low levels are detected in AML samples. Therefore, CD25 and ID4 mRNA expression might differentiate AML with BCR::ABL1 from BC-CML and assign it to the AML group. A method for identifying this new WHO entity is then proposed. Finally, the hypothesis of AML with BCR::ABL1 arising from driver mutations on a BCR::ABL1 background behaving as a clonal hematopoiesis mutation is discussed. Validation of our data in larger cohorts and basic research are needed to better understand the molecular and cellular aspects of AML with a BCR::ABL1 entity.

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“…Philadelphia chromosome positive (Ph + ) leukemia is a malignant clonal disease derived from hematopoietic stem cells, which is characterized by the expression of BCR-ABL fusion protein possessing strong tyrosine kinase activity [ 1 , 2 ]. Although tyrosine kinase inhibitors (TKI) are the only approved treatment option for Ph + leukemia, the nature of resistance, intolerance and recurrence has forced to evolve multiple generations of TKI, from imatinib to panatinib [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted degradation of oncogenic BCR-ABL by silencing the gene of NEDD8 E3 ligase RAPSYN

Sun,

Wang,

Liu

et al. 2024

J Nanobiotechnol

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Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target. Graphical Abstract

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Acquisition of the Ph chromosome and BCR-ABL fusion product in AML-M2 and t(8;21) leukemia: cytogenetic and FISH evidence for a late event

Cited by 21 publications

References 9 publications

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features

BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features

Deciphering Potential Molecular Signatures to Differentiate Acute Myeloid Leukemia (AML) with BCR::ABL1 from Chronic Myeloid Leukemia (CML) in Blast Crisis

Targeted degradation of oncogenic BCR-ABL by silencing the gene of NEDD8 E3 ligase RAPSYN

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