Childhood B-acute lymphoblastic leukemia: a genetic update

Abstract

In the pediatric population, B-acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy, as well as the leading cause of childhood cancer-related mortality. Advances in cytogenetics utilizing array-based technologies and next-generation sequencing (NGS) techniques have revealed exciting insights into the genetic basis of this disease, with the hopes of developing individualized treatment plans for affected children. In this comprehensive review, we discuss our current understanding of childhood (pediatric) B-ALL and highlight the most recent genetic advances and their therapeutic implications.

Keywords: B-cell; B-precursor; Cytogenetics; Genetics; Pediatric B-ALL.

Figure 1

Evaluation of a boy with abdominal pain, night sweats, increased fatigue, petechiae, and a white blood cell count of 113 × 10³/μL. A. Bone marrow core biopsy (100×) showed diffuse replacement of normal marrow elements by uniform sheets of round to oval lymphoblasts with indented to convoluted nuclei. B. Touch preparation of core biopsy material showed lymphoblasts with high nuclear to cytoplasmic (N:C) ratio, finely dispersed nuclear chromatin, and prominent nucleoli. C-D. Peripheral blood smear (100×) showed lymphoblasts with high N:C ratio and cytoplasmic pseudopods.

Figure 2

Evaluation of a 3 year-old boy with hyperdiploid B-ALL. A. Abnormal male hyperdiploid karyotype with extra copies of chromosomes X, 2, 9, 14. B. FISH analysis detected +9q, +14q and +21q in 96% , 93.7% and 96% of the nuclei examined, respectively. In addition, 12p deletion was observed in 89% of the nuclei examined, suggestive of an underlying complex aneuploid (most likely hyperdiploid) karyotype.

Figure 3

Evaluation of a 2 year-old girl presenting with fevers. A. Bone marrow core biopsy (100×) showing sheets of round to oval lymphoblasts. B. Bone marrow aspirate (100×) showing lymphoblasts with cytoplasmic vacuoles. C. Representative flow cytometry histogram. The CD45(dim) gated population contained excess B-lymphoblasts (81% of total), positive for CD10, CD19, CD34, CD38, CD79a, HLA-DR, and TdT. D. Abnormal female karyotype with unbalanced rearrangements of 1p, a derivative chromosome 12 (due to an unbalanced translocation between chromosomes 1p and 12p), and a derivative chromosome 21 (due to an unbalanced translocation between chromosomes 12 and 21), resulting in ETV6-RUNX1 fusion. E-F. Abnormal FISH signal pattern consistent with ETV6-RUNX1 (TEL-AML1) fusion, indicative of t(12;21) translocation.

Figure 4

Evaluation of a 3 year-old girl with pancytopenia. A. Bone marrow core biopsy (40×) showing sheets of lymphoblasts. B-C. Representative flow cytometry histograms. The CD45(dim) gated population contained excess and abnormal B-lymphoblasts (85% of the total), positive for CD10, CD13, CD19, CD22, CD34, CD38, HLA-DR, plus intracellular CD79a, intracellular CD22, and TdT. D. Abnormal composite female karyotype with monosomy 16, trisomy 21, and deletions of 6q and 9q. E. FISH analysis detected the ETV6-RUNX1 (TEL-AML1) fusion, indicative of t(12;21) translocation. In addition, 4.4% of these abnormal cells showed an extra copy of the RUNX1 locus, suggestive of an underlying +21q.

Figure 5

Evaluation of a 7 year-old boy with B-ALL. A. Abnormal male karyotype with a deletion of 11q and trisomy 21. B. FISH analysis demonstrated an abnormal signal pattern consistent with ETV6-RUNX1 (TEL-AML1) fusion, indicative of t(12;21) translocation, as well as +21q and 11q- (MLL deletion).

Figure 6

Evaluation of an 18 year-old female with B-ALL. A. Variably cellular marrow (100×) with clusters of B-lymphoblasts and reduced multilineage hematopoiesis. B. Representative flow cytometry histogram. The CD45(dim) gated population comprised approximately 4% of total cells and contained no excess blasts. C. Abnormal female karyotype demonstrating t(17;19) translocation. D. FISH analysis detected an abnormal signal pattern compatible with TCF3 (19p13) rearrangement.