Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1
Tracy Tucker, PhD, FCCMG
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.
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 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
• 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.
• CML patients in blast crisis can have a similar morphological appearance as MPAL with t(9;22).
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.
Deletions including IKZF1 (7p12.2) have been reported in MPAL with t(9;22).
Gene Mutations (SNV/INDEL)
Not known in this specific subgroup.
Not known in this specific subgroup.
Genes and Main Pathways Involved
• 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.
• 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.
• 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)
• The presence of t(9;22)(q34.1;q11.2) with mixed phenotype immune-profile is diagnostic of a cytogenetic subtype of MPAL.
• t(9;22)(q34.1;q11.2) MPAL have a poor prognosis and appears to be worse than that of the other MPALs. 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.
• Tyrosine kinase inhibitors such as imatinib or dasatinib.
• There are no biological factors that predict a patient’s response to tyrosine kinase inhibitors.
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