B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy

Abstract

B lymphoblastic leukemia/lymphoma (B-ALL) is a clonal hematopoietic stem cell neoplasm derived from B-cell progenitors, which mostly occurs in children and adolescents and is regarded as one of top leading causes of death related to malignancies in this population. Despite the majority of patients with B-ALL have fairly good response to conventional chemotherapeutic interventions followed by hematopoietic stem cell transplant for the last decades, a subpopulation of patients show chemo-resistance and a high relapse rate. Adult B-ALL exhibits similar clinical course but worse prognosis in comparison to younger individuals. Ample evidences have shown that the clinical behavior, response rate and clinical outcome of B-ALL rely largely on its genetic and molecular profiles, such as the presence of BCR-ABL1 fusion gene which is an independent negative prognostic predictor. New B-ALL subtypes have been recognized with recurrent genetic abnormalities, including B-ALL with intrachromosomal amplification of chromosome 21 (iAMP21), B-ALL with translocations involving tyrosine kinases or cytokine receptors (“BCR-ABL1-like ALL”). Genome-wide genetic profiling studies on B-ALL have extended our understanding of genomic landscape of B-ALL, and genetic mutations involved in various key pathways have been illustrated. These include CRLF2 and PAX5 alterations, TP53, CREBBP and ERG mutations, characteristic genetic aberrations in BCR-ABL1-like B-ALL and others. The review further provides new insights into clinical implication of the genetic aberrations in regard to targeted therapy development.

New targets for therapy: antigen identification in adults with B-cell acute lymphoblastic leukaemia

“…Different genetic alterations, such as aberrant expression of proto-oncogenes, chromosomal translocations, hypodiploidy and hyperdiploidy, all contribute to the leukaemic transformation of haematopoietic stem cells or their committed progenitors by changing cellular functions, such as normal proliferation, differentiation and apoptosis [2]. These primary oncogenic events are often insufficient by themselves to cause leukaemia and require secondary cooperative mutations.…”

“…The MLL gene is involved in more than 50 fusions, which may play a role in transformation of bone marrow cells through the regulation of HOX genes. The most frequent gene mutations found in B-ALL patient samples are those that affect the Ikaros family zinc finger protein 1 (IKZF1), a transcription factor and regulator of normal lymphoid development and differentiation [2].…”

“…Epratuzumab, a humanised anti-CD22 antibody, has appreciable anti-tumour activity and a good safety profile while Alemtuzumab is a fully humanised mAb against CD52. CD52, a cell surface glycoprotein, is involved in T-cell activation and is also expressed on pre-B ALL cells [2,5,7].…”

“…They bind to cell surface antigens and have the potential to enter the cerebrospinal fluid [1,7]. CD19-targeting CAR T cells have already proved to be powerful immunotherapy agents for B-ALL patients [2,7] despite differences in each trial in CAR design, conditioning regimens, leukaemia load, patient age, T-cell manufacturing and T-cell dosages [3,7,9,13]. All clinical trials reported toxicities including on-tumour off-target effects, CRS and neurotoxicity (referred to as immune effector cell (IEC)-associated neurotoxicity or ICANS).…”

A near‐haploid clone harboring a BCR/ABL1 gene fusion in an adult patient with newly diagnosed B‐lymphoblastic leukemia

“…Similar to hypodiploidy, the BCR/ABL1 gene fusion is considered an adverse prognostic finding in B‐ALL, although outcomes have significantly improved in the era of tyrosine kinase inhibitor (TKI) therapy . Most commonly the result of a balanced t(9;22)(q34.1;q11.2), the BCR/ABL1 gene fusion accounts for ~24% to 30% of adult B‐ALL and only 1‐3% in pediatric B‐ALL . Secondary cytogenetic abnormalities in BCR/ABL1 ‐positive B‐ALL are frequently observed and typically include in descending order: +der(22)t(9;22), +21, abnormalities of 9p, high hyperdiploidy, +8, −7, and +X .…”