Mixed-phenotype acute leukaemia 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:Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1.
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Primary Author(s)*
Tracy Tucker, PhD, FCCMG
Cancer Category / Type
HAEM4:Acute Leukemias of Ambiguous Lineage
Cancer Sub-Classification / Subtype
Mixed-phenotype acute leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1
Definition / Description of Disease
Mixed-phenotype acute leukemia (MPAL) with t(9;22) resulting in BCR-ABL1 gene fusion defines a subtype of MPAL, which are leukemias in which the blast cells show no clear differentiation along a single lineage and instead have both myeloid and lymphoid immunophenotypic markers[1].
In some cases of chronic myelogenous leukemia (CML), the blasts cells express both myeloid and lymphoid markers and thus would meet the criteria for MPAL, however, a prior diagnosis of CML should exclude patients from being classified as MPAL with t(9;22).
• t(9;22)(q34.1;q11.2) is a translocation involving the long arms of chromosomes 9 and 22 that is characteristic rearrangement in CML and also defines a distinctive cytogenetic subtype of acute lymphoblastic leukemia (ALL) and MPAL.
Synonyms / Terminology
Mixed-phenotype acute leukemia with t(9;22)(q34;q11.2)
Epidemiology / Prevalence
MPAL accounts for only 2-5% of all acute leukemias[2], however, MPAL with t(9;22) is the most common recurrent abnormality identified in 25% of adult MPAL cases[3] and in 3% of pediatric cases[4].
Clinical Features
Put your text here and fill in the table (Instruction: Can include references in the table)
| 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.MPAL with t(9;22) patients have a similar presentation to other patients with acute leukemia, and likely present similarly to t(9;22)-positive ALL patients with a high white blood cell count.
Sites of Involvement
Bone marrow
Morphologic Features
• Blasts must constitute 20% of all nucleated cells, but not necessarily of each distinct lineage.
• Blasts are dimorphic - resembling both lymphoblasts and myeloblasts.
• The vast majority of MPAL with t(9;22) cases have blasts that meet the criteria for B-cell and myeloid lineage leukemia[4].
• CML patients in blast crisis can have a similar morphological appearance as MPAL with t(9;22).
Immunophenotype
Put your text here and fill in the table (Instruction: Can include references in the table)
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE CD1 |
| Positive (subset) | EXAMPLE CD2 |
| Negative (universal) | EXAMPLE CD3 |
| Negative (subset) | EXAMPLE CD4 |
editv4:ImmunophenotypeThe content below was from the old template. Please incorporate above.The diagnosis of MPAL rests on the immunophenotypic features of blasts rather than morphology and flow cytometry.
The following are criteria for assigning more than one lineage to a single blast population:
- Myeloid lineage – MPO by flow cytometry, immunohistochemistry, or cytochemistry OR monocytic differentiation with two of the following: non-specific esterase, CD11c, CD14, CD64, lysozyme
- T-cell lineage – cytoplasmic or surface CD3 expression
- B-cell lineage – strong CD19 with one of the following strongly expressed: CD79a, cytoplasmic CD22, CD10 OR weak CD19 with two of the following strongly expressed: CD79a, cytoplasmic CD22, CD10
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.Almost all cases have a t(9;22) identified by karyotype analysis or a BCR-ABL1 fusion identified by FISH analysis. At the molecular level, the p190 fusion transcript is more common than the p210.
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence t(9;22)(q34;q11.2) 3'ABL1 / 5'BCR der(22) 2-5% of AML cases and 25% of all MPAL
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)
Diagnostic:
• The presence of t(9;22)(q34.1;q11.2) with mixed phenotype immune-profile is diagnostic of a cytogenetic subtype of MPAL.
Prognostic:• t(9;22)(q34.1;q11.2) MPAL have a poor prognosis and appears to be worse than that of the other MPALs[5][6]. It is unclear if patients with MPAL and t(9;22) have a worse prognosis than t(9;22)-positive ALL, however, some data exists to suggest that treatment with tyrosine kinase inhibitors would have a similar effect in MPAL as in ALL[7].
Therapeutic Target:• Tyrosine kinase inhibitors such as imatinib or dasatinib.
• There are no biological factors that predict a patient’s response to tyrosine kinase inhibitors.
Individual Region Genomic Gain / Loss / LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.)
| 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.Deletions including IKZF1 (7p12.2) have been reported in MPAL with t(9;22)[8].
Characteristic Chromosomal Patterns
Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis)
| 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.Many cases have other cytogenetic abnormalities in addition to the t(9;22) or a complex karyotype.
Gene Mutations (SNV / INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.)
| 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.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.Not known in this specific subgroup.
Epigenomic Alterations
Not known in this specific subgroup.
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.Genes:
• ABL1 on 9q34.12 is transcribed from centromere to telomere. It encodes a protein tyrosine kinase (SH1) which is regulated by its SH (SRC homology) domains (SH2, SH3) and has a DNA binding motif that is regulated by CDC2-mediated phosphorylation. It is widely expressed and has mainly a nuclear localization.
• BCR on 22q11.2 is transcribed from centromere to telomere. Its exact function is still unclear; it is known to contain an oligomerization domain, serine/threonine kinase activity, Rho guanine nucleotide exchange factor (RHO-GEF) domain, pleckstrin homology (PH) domain and a RAC-GAP domain. It is widely expressed and has mainly a cytoplasmic localization.
DNA:• t(9;22)(q34.1;q11.2) results in a 5’BCR-3’ABL1 hybrid gene with the functional fusion residing on the derivative 22. Several variants of the BCR-ABL1 fusion transcript are known. The most common variant (major variant, p210) fuses either BCR exon 13 or BCR exon 14 to ABL1 exon 2 (b2a2 and b3a2 respectively). The minor variant fuses BCR exon 1 to ABL1 exon 2 (p190, e1a2) whereas the micro variant fuses BCR exon 19 to ABL1 exon 2 (p230, e19a2). Fusions involving other exons of BCR or ABL1 are also possible.
Protein:• The p210 protein consists of amino acids 1-902 (or 927) from BCR linked to amino acid 1096 of ABL1. Both the p210 and p230 fusion proteins contain the RHO-GEF and PH domains from BCR, and the SH2 and SH3 domains, the kinase domain (SH1) and the DNA binding domain from ABL1. The fusion protein is predominantly located in nuclei and has constitutive kinase activity mediated by the oligomerization domain from BCR.
Key cellular pathways:• The chimeric protein encoded by the BCR-ABL1 fusion gene has constitutive kinase activity resulting in activation of the Ras signal transduction pathway.
• The PI3-K (phosphatidyl inositol 3' kinase) pathway is also activated via Ras.
• The aberrant signaling results in enhanced cellular proliferation of leukemic progenitors, inhibition of apoptosis and provokes cell adhesive abnormalities.
Genetic Diagnostic Testing Methods
• Chromosome analysis, FISH, RT-PCR
• FISH or RT-PCR is needed for cytogenetically cryptic cases with typical immunophenotype
• RT-PCR is employed for minimal residual disease detection
Familial Forms
None
Additional Information
None
Links
References
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- ↑ Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
- ↑ Weinberg, Olga K.; et al. (2014). "Mixed phenotype acute leukemia: A study of 61 cases using World Health Organization and European Group for the Immunological Classification of Leukaemias criteria". American Journal of Clinical Pathology. 142 (6): 803–808. doi:10.1309/AJCPPVUPOTUVOIB5. ISSN 1943-7722. PMID 25389334.
- ↑ Manola, Kalliopi N. (2013). "Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview". British Journal of Haematology. 163 (1): 24–39. doi:10.1111/bjh.12484. ISSN 1365-2141. PMID 23888868.
- ↑ 4.0 4.1 Al-Seraihy, Amal S.; et al. (2009). "Clinical characteristics and outcome of children with biphenotypic acute leukemia". Haematologica. 94 (12): 1682–1690. doi:10.3324/haematol.2009.009282. ISSN 1592-8721. PMC 2791935. PMID 19713227.
- ↑ Matutes, Estella; et al. (2011). "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification". Blood. 117 (11): 3163–3171. doi:10.1182/blood-2010-10-314682. ISSN 1528-0020. PMID 21228332.
- ↑ Killick, S.; et al. (1999). "Outcome of biphenotypic acute leukemia". Haematologica. 84 (8): 699–706. ISSN 0390-6078. PMID 10457405.
- ↑ Kawajiri, Chika; et al. (2014). "Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status". International Journal of Hematology. 99 (4): 513–518. doi:10.1007/s12185-014-1531-0. ISSN 1865-3774. PMID 24532437.
- ↑ Yan, Lingzhi; et al. (2012). "Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification". Haematologica. 97 (11): 1708–1712. doi:10.3324/haematol.2012.064485. ISSN 1592-8721. PMC 3487445. PMID 22581002.
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: “Mixed-phenotype acute leukaemia with BCR::ABL1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion.