B-lymphoblastic leukaemia/lymphoma with BCR::ABL1 fusion
Haematolymphoid Tumours (5th ed.)
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editHAEM5 Conversion NotesThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:B-Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
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Primary Author(s)*
Afia Hasnain, MBBS, PhD; Yassmine Akkari, PhD, FACMG
Cancer Category / Type
B-Lymphoblastic Leukemia/Lymphoma
Cancer Sub-Classification / Subtype
B-Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1
Definition / Description of Disease
B-Lymphoblastic Leukemia/Lymphoma with t(9;22)(q34.1;q11.2) is a neoplasm of lymphoblasts committed to the B-cell lineage in which the blasts harbor a translocation between BCR at 22q11.2 and ABL1 oncogene at 9q34.1. The t(9;22) results in the production of a BCR-ABL1 fusion, also known as the Philadelphia chromosome (Ph+).
Synonyms / Terminology
- Philadelphia chromosome
- Ph+
Epidemiology / Prevalence
- most common genomic alteration in adult B-ALL (25–30%)
- detected in only 2–4% of pediatric cases
Clinical Features
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| Signs and Symptoms | EXAMPLE Asymptomatic (incidental finding on complete blood counts)
EXAMPLE B-symptoms (weight loss, fever, night sweats) EXAMPLE Fatigue EXAMPLE Lymphadenopathy (uncommon) |
| Laboratory Findings | EXAMPLE Cytopenias
EXAMPLE Lymphocytosis (low level) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.The presenting features are generally similar to those seen in patients with other B-ALLs. Most children with B-ALL with BCR-ABL1 are considered to have high risk on the basis of age and white blood cell count (WBC). Patients tend to have a high WBC count at presentation, and although they may have organ involvement, lymphomatous presentations are rare.
Sites of Involvement
Bone marrow
Morphologic Features
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Immunophenotype
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| Finding | Marker |
|---|---|
| Positive (universal) | CD10, CD19 and TdT |
| Positive (subset) | CD13, CD33 and CD25 (in adults) |
| Negative (universal) | KIT (CD117) |
| Negative (subset) | EXAMPLE CD4 |
Chromosomal Rearrangements (Gene Fusions)
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| Chromosomal Rearrangement | Genes in Fusion (5’ or 3’ Segments) | Pathogenic Derivative | Prevalence | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE t(9;22)(q34;q11.2) | EXAMPLE 3'ABL1 / 5'BCR | EXAMPLE der(22) | EXAMPLE 20% (COSMIC)
EXAMPLE 30% (add reference) |
Yes | No | Yes | EXAMPLE
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.Put your text here and/or fill in the table
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(9;22)(q34.1;q11.2) 3'ABL1 / 5'BCR der(22)t(9;22) 25-30% in adults 2-4 % in pediatric cases
EXAMPLE t(8;21)(q22;q22) EXAMPLE 5'RUNX1 / 3'RUNXT1 EXAMPLE der(8) EXAMPLE 5%
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).Please incorporate this section into the relevant tables found in:
- Chromosomal Rearrangements (Gene Fusions)
- Individual Region Genomic Gain/Loss/LOH
- Characteristic Chromosomal Patterns
- Gene Mutations (SNV/INDEL)
The pediatric and adult Ph + B-ALL has been associated with the worst prognosis of the major cytogenetic subtypes of B- ALL. However, therapy with tyrosine kinase inhibitors (TKIs) has had a significantly favorable effect on outcome. A major molecular response is defined as a ≥3-log reduction in BCR-ABL1 transcript compared with the standardized baseline.
The presence of IKZF1 deletion has been associated with poor outcome and high risk of re- lapse. [1]
Individual Region Genomic Gain / Loss / LOH
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| Chr # | Gain / Loss / Amp / LOH | Minimal Region Genomic Coordinates [Genome Build] | Minimal Region Cytoband | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|
| EXAMPLE
7 |
EXAMPLE Loss | EXAMPLE
chr7:1- 159,335,973 [hg38] |
EXAMPLE
chr7 |
Yes | Yes | No | EXAMPLE
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference). |
| EXAMPLE
8 |
EXAMPLE Gain | EXAMPLE
chr8:1-145,138,636 [hg38] |
EXAMPLE
chr8 |
No | No | No | EXAMPLE
Common recurrent secondary finding for t(8;21) (add reference). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.The most common accompanying chromosomal abnormalities include monosomy 7 (including deletion of the IKZF1 gene) (18%), monosomy 9 or 9p deletion (9%), and gain of 1q (8%).
Chromosome Number Gain/Loss/Amp/LOH Region 7 Loss chr7:1-159,345,973 9 Loss chr9:1-138,394,717
Characteristic Chromosomal Patterns
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| Chromosomal Pattern | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|
| EXAMPLE
Co-deletion of 1p and 18q |
Yes | No | No | EXAMPLE:
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.The t(9;22) results in the production of a BCR-ABL1 fusion protein. The majority of pediatric and half of adult t(9;22) positive B-ALL involve the minor breakpoint cluster region (m-bcr) encoding a smaller p190 fusion protein in contrast to chronic myelogenous leukemia (CML), where it involves the major breakpoint cluster region (M-bcr). [2]
Gene Mutations (SNV / INDEL)
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| Gene; Genetic Alteration | Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) | Prevalence (COSMIC / TCGA / Other) | Concomitant Mutations | Mutually Exclusive Mutations | Diagnostic Significance (Yes, No or Unknown) | Prognostic Significance (Yes, No or Unknown) | Therapeutic Significance (Yes, No or Unknown) | Notes |
|---|---|---|---|---|---|---|---|---|
| EXAMPLE: TP53; Variable LOF mutations
EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations |
EXAMPLE: TSG | EXAMPLE: 20% (COSMIC)
EXAMPLE: 30% (add Reference) |
EXAMPLE: IDH1 R123H | EXAMPLE: EGFR amplification | EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).
|
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
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Genes and Main Pathways Involved
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| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| EXAMPLE: BRAF and MAP2K1; Activating mutations | EXAMPLE: MAPK signaling | EXAMPLE: Increased cell growth and proliferation |
| EXAMPLE: CDKN2A; Inactivating mutations | EXAMPLE: Cell cycle regulation | EXAMPLE: Unregulated cell division |
| EXAMPLE: KMT2C and ARID1A; Inactivating mutations | EXAMPLE: Histone modification, chromatin remodeling | EXAMPLE: Abnormal gene expression program |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.BCR and ABL1
Genetic Diagnostic Testing Methods
- Clinical testing for the BCR-ABL1 fusion includes conventional chromosome studies, dual color, dual fusion FISH analysis and RT- PCR.
- FISH results can be available within 24 h and should be considered as the first line test.
- Quantitative RT-PCR can detect specific transcripts at a higher sensitivity, and important at follow up to determine disease status and degree of response.
- Conventional cytogenetics can also detect variant translocations, additional Philadelphia chromosome resulting in gain of 9q and 22q as well as trisomy 8, and a hyperdiploid karyotype.
- CMA cannot detect balanced rearrangements such as t(9;22) but it can detect additional copy number abnormalities.
- An average of 7.8 lesions per case were observed by using CMA in adults with Ph + B-ALL.[3]
Familial Forms
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Additional Information
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Links
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References
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- ↑ van der Veer, Arian; et al. (2014-03-13). "IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL". Blood. 123 (11): 1691–1698. doi:10.1182/blood-2013-06-509794. ISSN 1528-0020. PMID 24366361.
- ↑ Woo, Jennifer S.; et al. (2014). "Childhood B-acute lymphoblastic leukemia: a genetic update". Experimental Hematology & Oncology. 3: 16. doi:10.1186/2162-3619-3-16. ISSN 2162-3619. PMC 4063430. PMID 24949228.
- ↑ Fedullo, Anna Lucia; et al. (02 2019). "Prognostic implications of additional genomic lesions in adult Philadelphia chromosome-positive acute lymphoblastic leukemia". Haematologica. 104 (2): 312–318. doi:10.3324/haematol.2018.196055. ISSN 1592-8721. PMC 6355475. PMID 30190342. Check date values in:
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Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome. *Citation of this Page: “B-lymphoblastic leukaemia/lymphoma with BCR::ABL1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:B-lymphoblastic_leukaemia/lymphoma_with_BCR::ABL1_fusion.