Table of ContentsDefinition / general | Essential features | Terminology | Clinical features | Uses by pathologists | Prognostic factors | Molecular / cytogenetics description | Sample pathology report | Board review style question #1 | Board review style answer #1
Cite this page: Ding Y. BCR::ABL1. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/molecularBCRABL.html. Accessed June 4th, 2023.
Definition / general
- Philadelphia chromosome (Ph) results from a reciprocal translocation between chromosomes 9 and 22[t(9;22)] that gives rise to a BCR::ABL1 fusion gene (Nature 1973;243:290)
- BCR::ABL1 fusion proteins demonstrate increased tyrosine phosphokinase activity; patients with these mutations may have clinical response to kinase inhibitor therapy (e.g., imatinib, nilotinib, dasatinib) (N Engl J Med 2001;344:1031)
- Depending on the breakpoint of BCR gene on chromosome 22, different size segments are joined with the 3' sequences of the ABL1 proto-oncogene on chromosome 9 and may influence the disease phenotype (Blood 1996;88:2375)
- There are major (M bcr, includes e13a2 and e14a2), minor (m bcr, e1a2), μ (μ bcr, e19a2) and micro breakpoints, each of which result in different size mRNA fusion transcripts and protein products (p210, p190 or p230)
|Breakpoint of BCR::ABL1 fusion||mRNA fusion transcripts||Protein products|
|M BCR||e13a2, e14a2||p210|
- Breakpoint cluster region (BCR)
- Abelson murine leukemia viral oncogene homolog 1 (ABL1)
- BCR::ABL1 or Ph chromosome is observed in:
- 90 - 95% of patients with chronic myeloid leukemia (CML); mostly p210 (mRNA fusion transcripts e13a2 and e14a2) and rarely p230 (mRNA fusion transcript e19a2)
- Up to 20 - 30% of adults with acute lymphoblastic leukemia (B-ALL), about half with p210 and remaining half with p190 (mRNA fusion transcript e1a2); 5% of children with B-ALL, mostly p190 (Blood 1996;88:2375)
- Up to 1 - 2% of patients with acute myeloid leukemia (AML); mostly p210, minority p190 (Leuk Lymphoma 2013;54:138)
Uses by pathologists
- Aids in diagnosis, such as chronic myeloid leukemia (CML) or BCR::ABL1 positive ALL, etc. (Nature 1973;243:290, Arch Pathol Lab Med 2020;144:150)
- Monitor of tyrosine kinase inhibitor (TKI) treatment response (Cancer Cell 2020;37:530)
- If left untreated, the median survival rate of CML is around 2 - 3 years
- Several tyrosine kinase inhibitors (TKIs) are approved as first line treatment for chronic phase CML, which has significantly improved the prognosis with up to 70% of people having a complete cytogenetic response (see Molecular / cytogenetics description) 1 year after starting a TKI
- CML patients with > 10% BCR::ABL international scale (IS) at 6 and 12 months are considered to have TKI resistant disease, which should be considered second line therapy or allogeneic hematopoietic cell transplant (HCT)
- Ph positive B-ALL is associated with poor prognosis and identified as very high risk
- AML with BCR::ABL1 rearrangement is rarely de novo and associated with poor / adverse risk; these patients may benefit from TKI therapy
Molecular / cytogenetics description
- BCR::ABL1 fusion gene is usually detected by cytogenetics, FISH, reverse transcription PCR and next generation sequencing (NGS)
- In CML, quantifiable BCR::ABL1 p210 transcript level using international scale (IS) is used in initial workup and for monitoring efficacy of therapy or minimal / measurable residual disease (MRD)
- During disease monitoring:
- 2 log reduction from the standard baseline (100% IS) generally correlates with complete cytogenetic response (CCyR) (≤ 1% IS)
- ≥ 3 log reduction (≤ 0.1% IS) is referred to as major molecular response (MMR or MR3.0)
- > 4.5 log reduction (< 0.0032% IS) is referred to as complete molecular response or molecular remission (CMR or MR)
- Log reduction = log10(average BCR::ABL1/ABL1 of newly diagnosed CML) - log10(BCR::ABL1/ABL1 of patient's sample)
- There is no international scale established for other BCR::ABL1 isoforms, such as p190 and p230
Sample pathology report
- BCR::ABL1 p210 result: 22.4% IS
- BCR::ABL1 p210 result interpretation:
- The BCR::ABL1 p210 fusion transcript (e13a2 or e14a2) is detected.
- Clinical significance: This assay is intended for use as an aid in the diagnosis and management of BCR::ABL1 p210 positive chronic myeloid leukemia (CML), B lymphoblastic leukemia / lymphoma (B ALL / LBL) and other leukemic patients with Philadelphia chromosome (Ph), including those undergoing kinase inhibitor therapy (e.g., imatinib, nilotinib, dasatinib). This test may be used to monitor efficacy of therapy or minimal / measurable residual disease (MRD) and is not recommended as a sole primary diagnostic test for CML or acute leukemia. The trend of these results over time is more informative of disease status than an individual result (1 - 4).
- In CML, this assay provides important information about quantifiable BCR::ABL1 p210 transcript level using international scale (IS) at initial workup and for monitoring response to therapy. Of note, the BCR::ABL1 p210 and p190 can coexist in CML.
- Methodology: Peripheral blood samples, bone marrow samples or extracted RNA samples are directly tested using integrated RNA isolation, reverse transcription and nested real time PCR of BCR::ABL1 target gene and ABL1 reference gene to detect BCR::ABL1 fusion transcripts e13a2.
- The limit of detection (LoD) for the assay is 0.003% IS, as determined by _______ Molecular Diagnostics Laboratory. This test does not discriminate between the e14a2 (b3a2) and e13a2 (b2a2) variant transcripts.
Board review style question #1
Which of the following genes acts as an oncogene?
Board review style answer #1
B. BCR::ABL1. All of the rest (APC, BRCA1, NF1 and TP53) are tumor suppressor genes, for which loss of function results in increased cancer risk.