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تسجيل

Acute Lymphoblastic Leukemia: Somatic Mutations

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P870

2026-09-09

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The most commonly altered pathways in ALL, involving the transcriptional regulation of lymphoid development, such as PAX5 (9p13.2), IKZF1 (7p12.2), and EBF1 (5q33.3), are frequently mutated (Chapter 66). PAX5 is required for B-lymphoid lineage commitment and maturation. PAX5 genetic alterations include deletions, sequence mutations, and chimeric genes with at least 16 different chromosomal partners (http://atlasgeneticsoncology.org/Genes/ PAX5ID62.html). IKZF1 is required for the development of all lymphoid lineages and its genetic lesions are implicated in resistance to chemotherapy and TKIs.

Other commonly mutated pathways in ALL include genes involved in tumor suppression and cell cycle regulation (TP53, Rb1, and CDKN2A), cytokine receptor, RAS-signaling, lymphoid signaling, and epigenetic modification such as EZH2. An integrated approach including NGS and array studies has con tributed to an increased number of novel molecular entities such as DUX4/ERG, ETV6-RUNX1-like ALL, and MEF2D/ZNF384 ALL. Rearrangements of DUX4, a homeobox transcription factor (4q35.2) such as overexpression, or transcription binding causing a loss of function of ERG (21q22.2) is present in 4% to 7% of B-cell-ALL. Aside from ERG deletion, DUX4 fusions are frequently accompanied by IKZF1, PAX5, and 9p deletions and by activating mutations in NRAS, KRAS, and MYC. Another novel form, ETV6-RUNX1-like ALL, is characterized by ETV6 and IKZF1 aberrations and approximately 3% to 5% of all child hood B-cell ALL belong to this new biological category. This integrated approach revealed that MEF2D (1q1.3) and ZNF38 (12p13.1) fusions as recurrent events both in adult (∼7%) and pediatric (3.6%) ALL and that they should be considered as two distinct expression subgroups. MEF2D fusions identify a group of patients with upregulation of HDAC9 both in children and adults which is associated with a poor outcome. The expression subgroup of patients with ZNF384 fusions is observed in patients with hyper-expression of JAK-STAT signaling pathways genes, and of GATA3 and CEBPA/B.