Acute Lymphoblastic Leukemia FISH Probes
Aberrations in the long arm of chromosome 6 are common in ALL. MYB, located at 6q23, has been found amplified in up to 8.4% of T-cell ALL. SEC63, located at 6q21, is deleted in about 16% of adult ALL.
While ABL1's best known fusion partner in most leukemias is BCR, it has also been found fused to several other genes in ALL, including ETV6 and NUP214. These fusions promote disease progression by providing proliferation and survival advantages to lymphoblasts.
Ph-like ALL is characterized by rearrangements in kinase and cytokine receptor genes that contribute to its activated kinase profile. ABL2 has recently been identified as an ABL-class gene that can produce these activating kinase fusions in ALL. Fusion partners reported so far include ETV6 and RCSD1.
Philadelphia chromosome (Ph)/BCR/ABL-positive ALL is the most common genetic subtype in adult ALL; approximately 25-40% of patients have a malignant clone expressing the Ph chromosome. Prevalence increases with age and is associated with poor outcome.
Our BCR/ABL1/ASS1 probe is also designed to detect BCR/ABL1 fusions, with the ASS1 probe added to detect 9q34 deletions that have been shown to be associated with t(9,22).
Extra copies of chromosome 4 are recurrent in pediatric ALL. The abnormality rarely occurs as the sole alteration, and is tightly associated with high hyperdiploidy.
Pediatric ALL is characterized by gains of several chromosomes, including chromosome 6. The oncogenic consequences of these gains aren’t completely understood, but it’s suspected that gene dosage effects play a role.
Recent research indicates that chromosome 10 trisomy occurs in up to 60% of pediatric hyperdiploid pediatric ALL patients. The alteration is correlates with favorable prognosis in this group.
Chromosome 17 gains are found in up to 77% of hyperdiploid childhood ALL patients, according to recent studies. It’s one of the most frequent aneusomies found in this subtype.
Overexpression of the CRLF2 protein is frequent in B-ALL cases that lack rearrangements in many common leukemia-associated genes, including TEL, MLL, TCF3, and BCR/ABL1, and usually occurs via CRLF2 rearrangement (either translocation or intrachromosomal deletion).
CSF1R is one of several kinase genes found recurrently arranged in Ph-like ALL. Translocations result in constitutively activated kinase fusions. MEF2D and SSBP2 are two well-documented CSF1R fusion partners in ALL.
EPOR rearrangements are most common in Ph-like ALL. Resulting abnormal EPOR expression leads to hypersensitivity to erythropoietin stimulation and upregulated JAK-STAT activation.
ETV6/RUNX1 fusion occurs in roughly a quarter of pediatric B-cell ALL cases. It’s found predominantly in children, and is rarely detected in adolescents and young adults.
IGH translocations are present in nearly in all cases of B-ALL, specifically t(8;14)(q24;q32) and its variants t(2;8)(p12;q24) and t(8;22)(q24;q11). These rearrangements all result in overexpression of the IGH fusion partner via IGH promotion, and are especially common in teenagers and young adults.
Recent studies indicate that JAK2 rearrangements occur in up to 7% of Ph-like ALL, most frequently in young adults. These translocations produce fusions with activated JAK-STAT signaling pathways and confer cytokine-independent proliferation.
MLL translocations, found in roughly 8% of adult B-ALL, produce chimeric proteins with the N-terminal portion of MLL fused to the C-terminal portion of a fusion partner. These fusions alter the expression of HOX genes, leading to aberrant self-renewal and growth of hematopoietic stem cells and progenitors.
CDKN2A is a cell cycle regulator and critical tumor suppressor. The gene is deleted in both B- and T-lineage ALL; 9p deletions occur in up to 15% of adult ALL, and are the most prevalent aberration (behind BCR/ABL1) in the disease.
PAX5 is an important regulator of early B-cell differentiation. Because of its role in B-cell development, alterations in the gene can promote disease development. One study found that complete deletion of one PAX5 allele occurs in 15% of adult BCP-ALL.
TCF3 plays a role in several ALL fusions, the most common being t(1;19), which fuses TCF3 to PBX1. The fusion is found in 3-5% of ALL. The majority of TCF3/PBX1 BCP-ALLs are pre-B-cell receptor positive, and expression of pre-B-cell receptor genes are directly upregulated by the fusion.