B-Lymphoblastic Leukemia/Lymphoma, BCR-ABL1-Like
Mark G. Evans, MD, University of California, Irvine
Fabiola Quintero-Rivera, MD, University of California, Los Angeles
Acute Lymphoblastic Leukemia
Cancer Sub-Classification / Subtype
B-lymphoblastic leukemia/lymphoma, BCR-ABL1-like
Definition / Description of Disease
In 2009, a high-risk subgroup of B-ALL was identified in children, adolescents, and young adults. The genetic expression is similar to that of BCR-ABL1-positive cases, but without t(9;22)(q34.1;q11.2). Instead, BCR-ABL-1-like B-ALL is a genetically heterogenous disease, often with alterations activating cytokine receptors and tyrosine kinases. Several genetic expression profiles were initially utilized to recognize cases, however, different profiles did not always identify the same patients. Although emerging data advocates the therapeutic use of tyrosine kinase or JAK inhibitors in this disease process, BCR-ABL-like B-ALL is often associated with very high rates of relapse and poor overall survival; thus proper diagnosis is essential.
Synonyms / Terminology
Ph-like B-lymphoblastic leukemia/lymphoma
Epidemiology / Prevalence
- Ph-like ALL comprises up to 15% of childhood B-ALL, and 20 to 25% in adolescents and young adults.
- The incidence in adult patients is controversial—from 13-17% to up to 33% in some reports.
- Higher rates of disease are observed in Hispanic and Native-American populations, and among children with Down syndrome.
The presenting symptoms are similar to those of other ALL patients, with the exception of potentially higher white blood cell counts.
Sites of Involvement
There are no morphological or cytochemical features that aid in the diagnosis. Blasts range from small to large and chromatin varying from immature to more mature, corresponding to French-American-British classification L1 or L2 subtype.
Blasts are typically CD19, TdT, and CD10-positive. By flow cytometry, a subset of cases with CRLF2 translocations show very high levels of surface protein expression.
Chromosomal Rearrangements (Gene Fusions)
Tyrosine kinase-type translocations are common and involve ABL1 and other kinases (such as ABL2, EPOR, JAK2, PDGFRB, and CSF1R); more than 30 gene partners have been described. Frequently reported examples include IGH–EPOR of the t(14;19)(q32;p13)/ins(14;19)(q32;p13), EBF1–PDGFRB of the del(5)(q32q33.3), NUP214–ABL1 of the t(9;9)(q34;q34)/del(9)(q34q34), and ETV6–ABL1 of the t(9;12)(q34;p13). Other notable fusions are BCR–JAK2, PAX5–JAK2, STRN3–JAK2, RANBP2–ABL1, RCSD1–ABL1, and MEF2D–CSF1R.
Characteristic Chromosomal Aberrations / Patterns
Approximately half of cases demonstrate rearrangements resulting in overexpression of CRLF2. These rearrangements are the result of either translocation of immunoglobin heavy chain enhance locus into CRLF2 (IGH-CRLF2—more commonly seen in adults) or through a cryptic deletion on chromosome X/Y involving the PAR1 psuedoautosomal region, resulting in fusion of CRLF2 to P2RY8 (more commonly seen in children). Very rare alternative translocations involving CRLF2 have also been observed.
[Abnormal FISH results in interphase nuclei from a bone marrow sample using the CRLF2 dual-color, break-apart (Cytocell) and IGH dual-color, break-apart probes, reflective of IGH-CRLF2 fusion]
[Concurrent abnormal karyotype with trisomy 21 and a translocation involving chromosomes X, 14, and 2 in 9 of 13 cells available for analysis. Metaphase FISH with the IGH break-apart probe (Vysis) confirms the presence of 5’ IGH (green signal) on the abnormal chromosome Xp33.1 (CRLF2 locus), highly suggestive on an IGH-CRLF2 fusion rearrangement.
(Images courtesy of Fabiola Quintero-Rivera, MD)
Monoallelic (often partial) deletion of the IKAROS transcription factor, encoded by IKZF1, is one of the most frequently observed genetic abnormalities in BCR-ABL1-like B-ALL, although this finding is not specific and not included in the definition.
Gene Mutations (SNV/INDEL)
In addition to gene translocations, gain-of-function mutations in CRLF2 itself or in its partner gene, IL7RA, have been seen. Alternative alterations activating kinase signaling occur, including activating mutations of FLT3, as well as focal deletions of SH2B3 (also known as LNK).
Herold et al. in 2017 reported a wide variety of molecular alterations in BCR-ABL1-like B-ALL, which was shown to have statistically significant associations with alterations of IKZF1, CRLF2, JAK2, BTG1, and high CRLF2 expression.
Genes and Main Pathways Involved
- IKAROS transcription factor: Deletion of IKZF1 results in activation of EBF1, MSH2, and MCL1, leading to B-cell leukemogenesis.
- CRLF2 overexpression: CRFL2 and its cofactor IL7RA form a receptor for thymic stromal-derived lymphopoietin that activates the JAK2-signal transducer and upregulates the transcription 5 pathway.
- Dysregulation of several tyrosine kinase signaling pathways (involving ABL1, ABL2, PDGFRB, CSF1, etc.) results in B-cell progenitor proliferation.
Diagnostic Testing Methods
- Flow cytometry for CRLF2 has been shown in some studies to be 100% concordant with FISH results.
- Next-generation sequencing is helpful for detecting copy number changes, single nucleotide variants, and gene fusions involving CRLF2, ABL1, ABL2, JAK2, etc.
- Gene expression profile algorithms, incorporating prediction analysis or hierarchical clustering of microarrays, provide the definitive diagnosis of BCR-ABL1-like B-ALL.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
- Diagnosis: Definitive diagnosis is based on two major gene expression signatures (DCOG/Erasmus MC and COG/St. Jude).
- DCOG/Erasmus MC incorporates hierarchal clustering of microarrays using a 110-gene probe set; this genetic signature frequently detected deletions in IKZF1, dic(9;20), and iAMP21 in BCR-ABL1-like B-ALL.
- COG/St. Jude employs predictive analysis of microarrays using a 257-gene probe set; this genetic signature demonstrated primarily activating kinase or cytokine receptor signaling alterations, in addition to IKZF1 deletions.
- Prognosis: In both pediatric and adult populations, BCR-ABL1-like B-ALL is associated with high rates of relapse and poor prognosis.
- The median 5-year overall survival rates for children with BCR-ABL1-like B-ALL, adolescents, and young adults was 72.8%, 65.8%, and 25.8%, respectively.
- Median 5-year-overall survival in adults was 22%, versus 64% in comparable patients with non-BCR-ABL1, non-BCR-ABL1-like, and non-MLL translocation B-ALL.
- Therapeutic Implications: Due to the aggressive nature of the disease, patients are often treated with high-intensity chemotherapy regimens, such as hyper-CVAD or an augmented Berlin-Frankfurt-Münster regimen.
Families with certain inherited variants of GATA3 (often seen in Native-American populations) are at increased risk of BCR-ABL1-like B-ALL.
Pre-B ALL B-lymphoblastic leukemia/lymphoma with BCR-ABL1-like/Ph-like in Pathology Outlines (http://www.pathologyoutlines.com/topic/leukemiaprebbcrabl1like.html)
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