Complex karyotype with cryptic FUS gene rearrangement and deletion of NR3C1 and VPREB1 genes in childhood B‑cell acute lymphoblastic leukemia: A case report

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is a hematopoietic malignancy characterized by overproduction of immature B-lymphoblasts. BALL is the most common pediatric tumor and remains the leading cause of mortality in children and adolescents. Molecular and cytogenetic analyses of BALL revealed recurrent genetic and structural genomic alterations which are routinely applied for diagnosis, prognosis and choice of treatment regimen. The present case report describes a 4-year-old female diagnosed with BALL. GTG-banding at low resolution revealed an abnormal clone with 46,XX,?t(X;19)(q13;q13.3),der(9) besides normal cells. Molecular cytogenetics demonstrated a balanced translocation between chromosomes 16 and 19, and an unbalanced translocation involving chromosomes 5 and 9. A locus-specific probe additionally identified that the FUS gene in 16p11.2 was split and its 5' region was translocated to subband 19q13.33, whereas the 3' region of the FUS gene remained on the derivative chromosome 16. Overall, this complex karyotype included four different chromosomes and five break events. Further analyses, including array-comparative genomic hybridization, additionally revealed biallelic deletion of the tumor suppressor genes CDKN2A/B, and deletion of the NR3C1 and VPREB1 genes. The patient passed away under treatment due to sepsis.

IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B‐lymphoblastic leukemia

“…For example, B‐ALL characterized by an ETV6 :: RUNX1 rearrangement or hyperdiploidy with double trisomy has an excellent survival rate of 93%, and may be treated with less intensive therapy than other subtypes 17,18 . On the other hand, KMT2A rearrangement, BCR::ABL1 (Philadelphia chromosome) rearrangement (Ph + ), and Philadelphia‐like (Ph‐like, e.g., CRLF2 rearrangement, often with IKZF1 deletion) are among the subtypes associated with less favorable prognoses 19–24 …”

“…17,18 On the other hand, KMT2A rearrangement, BCR::ABL1 (Philadelphia chromosome) rearrangement (Ph + ), and Philadelphia-like (Ph-like, e.g., CRLF2 rearrangement, often with IKZF1 deletion) are among the subtypes associated with less favorable prognoses. [19][20][21][22][23][24] We have previously shown that concomitant CRLF2 rearrangement and IKZF1 deletion are associated with H/L ethnicity. 25 In the current study, we sought to identify novel genetic drivers and secondary genetic alterations in B-ALL associated with H/L ethnicity.…”

A new childhood ALL case with an extremely complex karyotype and acute spontaneous tumor lysis syndrome

“…Interestingly CK in B-ALL is defined with ≥ 5 abnormalities [ 8 ]. CKs have been incorporated into the definition of high-risk ALL and many studies have suggested new definitions based on affected regions or types of aberrations [ 9 , 10 ]. However, their prognostic significance has not been consistently validated in large series.…”

Mutational Analysis of the VPREB1 Gene of Pre-BCR Complex in a Cohort of Sporadic Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia

“…These genes include a large number of transcription factors and transmembrane receptors, such as Notch1, E2A, CRLF2, EBF1, BTK, JAK2, λ5, BLNK, PIK3R1, IKZF1, PAX5, and VPREB1 10–12. Among them, the association of specific gene alterations and deletions such as IKZF1 and VPREB1 with ALL prognoses has been identified 13,14. The differentiation of precursor BCR (pre-BCR) involves a complex combination of expression of intracellular and cell surface markers with the rearrangement of the immunoglobulin heavy (H) and light (L) chain genes, and association of heavy chain with surrogate light chains (SLC) or pseudo light chain containing VPREB1 and λ5 proteins and signaling subunits Igα and Igβ 15,16.…”

“…[10][11][12] Among them, the association of specific gene alterations and deletions such as IKZF1 and VPREB1 with ALL prognoses has been identified. 13,14 The differentiation of precursor BCR (pre-BCR) involves a complex combination of expression of intracellular and cell surface markers with the rearrangement of the immunoglobulin heavy (H) and light (L) chain genes, and association of heavy chain with surrogate light chains (SLC) or pseudo light chain containing VPREB1 and λ5 proteins and signaling subunits Igα and Igβ. 15,16 These processes are represented as the first checkpoint in B-cell development.…”