Entire ABL1 Gene Deletion Without BCR/ABL1 Rearrangement in a Female Patient with B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant disease characterized by lymphocytic B-line or T-line cells abnormally proliferating in the bone marrow or extramedullary sites. BCR/ABL1 fusion protein in patients with ALL accounts for acts in 15-30% of B-lineage ALL cases, usually in adolescence. However, entire ABL1 gene deletion without BCR/ABL1 rearrangement is a rare phenomenon in ALL patients. Here we describe the first case of entire ABL1 gene deletion without BCR/ABL1 rearrangement in a female B-ALL patient. Relevant literature is reviewed to explain the association between ABL1 deletion and the pathogenesis/prognosis of this disease. ABL gene deletion can repress the activation of p53 and p73, and disrupt TGF-β signaling pathway to allow malignant cells to invade the normal tissue. The clinical significance of ABL gene deletion needs to be further explored.

Keywords: ABL1 deletion; ALL; acute lymphoblastic leukemia; pathogenesis; prognosis.

Figure 1

(A) The new diagnosis of bone marrow smears showed that lymphoblast and prolymphocyte accounted for 87%. (B) The Myelogram showed no blast cell after the systemic chemotherapy.

Figure 2

Chromosome study showing a normal female karyotype, 46,XX.

Figure 3

(A) FISH using BCR-ABL dual-color, dual-fusion translocation probe at diagnosis. Two green signals (BCR gene) are present, but only one red signal (ABL gene) is found. (B) FISH using ABL1 probe at diagnosis. Green signal represents 5ʹABL1 and red signal represents 3ʹABL1.

Figure 4

Copy number variations (CNV) analysis based on next-generation sequencing (NGS). Log2>0.5: gene copy number significantly increased; Log2<-0.5: gene copy number significantly deleted. The reduction in the copies of ABL1 gene on the long arm of chromosome 9, EVT6 gene on the short arm of chromosome 12 and DLEU2 gene on the long arm of chromosome 13; the increase in the copies of RET, PTEN, NT5C2 and SMC3 on the long arm of chromosome 10.

Figure 5

On one hand, the phosphorylation of HDM2 by c-Abl activated kinase alters the signal transduction of Hdm2-p53, promoting the stabilization and activation of P53. On the other hand, c-Abl phosphorylation of Hdm2 increases Hdm2-HdmX complex formation and promotes MDM2-directed MDMX ubiquitination, promoting p53 activation.

Figure 6

The phosphorylation of YAP1 by c-Abl activated kinase transfers its co-activator function from proliferation-driving TEAD transcription factors to p73, and then promote the transcription of apoptotic target genes.

Figure 7

TGF-β signaling stimulates the secretion and activation of matrix metalloproteinases (MMPs) to remodel the extracellular matrix (ECM), then allowing malignant cells to penetrate the normal tissue. However, ABL activation can suppress the expression and secretion of MMPs through inhibiting TGF-β signaling and protect tumor cells from invading the tissue.