HAEM4Backup:Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
Primary Author(s)*
Tracy Tucker, PhD, FCCMG
Cancer Category/Type
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
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
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)
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 |
Characteristic Chromosomal Aberrations / Patterns
Many cases have other cytogenetic abnormalities in addition to the t(9;22) or a complex karyotype.
Genomic Gain/Loss/LOH
Deletions including IKZF1 (7p12.2) have been reported in MPAL with t(9;22)[5].
Gene Mutations (SNV/INDEL)
Not known in this specific subgroup.
Epigenomics (Methylation)
Not known in this specific subgroup.
Genes and Main Pathways Involved
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.
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
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
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[6][7]. 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[8].
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.
Familial Forms
None
Other Information
None
Links
References
- ↑ 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.
- ↑ 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.
- ↑ 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.
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.