What are the genetic-molecular characteristics of anaplastic large cell lymphoma (ALCL)?

Updated: May 08, 2020
  • Author: Delong Liu, MD, PhD; Chief Editor: Emmanuel C Besa, MD  more...
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Most patients (60-70%) with the primary systemic anaplastic large cell lymphoma (ALCL) have translocation between chromosomes 2 and 5, resulting in a fusion protein that joins the N-terminus of nucleophosmin (NPM) to the C-terminus of anaplastic lymphoma kinase (ALK). The wild-type NPM protein has ubiquitous expression and functions as a carrier of proteins from the cytoplasm into the nucleolus. The ALK wild type has its postnatal expression limited to a few cells in the nervous system and functions as a tyrosine kinase receptor. [18, 19]

The 2;5 translocation brings the ALK gene portion encoding the tyrosine kinase on chromosome 2 under control of the NPM promoter on chromosome 5, producing permanent expression of the chimeric NPM-ALK protein (p80). This protein, an aberrant tyrosine kinase, presumably triggers malignant transformation via constitutive phosphorylation of intracellular targets. The presence of NPM-ALK serves as an additional diagnostic and subclassification tool for ALCL.

Less common ALK fusion proteins associated with ALCL include those resulting from t(1;2), t(2;3), inv(2), and t(2;22). All variants demonstrate linkage of the ALK tyrosine kinase domain to an alternative promoter that regulates its expression.

ALK-positive systemic ALCL is relatively less aggressive and carries a better prognosis than ALK-negative systemic ALCL.

Primary cutaneous-ALCL is typically ALK negative. However, a few cases with ALK positivity have been reported with similar prognosis.

Translocations involving the IRF4 (interferon regulatory factor-4) gene locus, also known as multiple myeloma oncogene-1 (MUM1), have been reported in peripheral T-cell lymphoma not otherwise specified (NOS) and primary cutaneous ALCL. These translocations were rarely found in systemic ALCL and thus can be used to differentiate between these entities.

ALK-positive and ALK-negative ALCLs have been found to have different gene-expression profiles. BCL6PTPN12CEBPB, and SERPINA1 genes are overexpressed preferentially in ALK-positive ALCLs, whereas CCR7CNTFRIL22, and IL21 genes are overexpressed preferentially in ALK-negative ALCLs. [11, 20]

A study by Larose et al demonstrated the importance of the Notch pathway in ALCL. Using whole-exome sequencing and gene set enrichment analysis, these researchers detected variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, in 12% of ALCL patient samples (both ALK positive and ALK negative). [21]

Treatment directed at NOTCH1—inhibition with gamma-secretase inhibitors or silencing by short hairpin RNA (shRNA)—leads to apoptosis, and in vitro, co-treatment with the ALK inhibitor crizotinib had additive/synergistic anti-tumor activity suggesting that the Notch pathway is a suitable target for second-line therapy in ALK-positive ALCL. [21]

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