NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target

Abstract

Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is the current challenge.

Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice

“…The diagnosis of PTCL is one of the most challenging among lymphomas and more often results in an inconclusive, inconsistent, or incorrect diagnosis. [19][20][21]32,33 Recently, novel therapeutic approaches have shown striking benefits in subgroups of PTCL, including brentuximab vedotin on CD301 PTCL, particularly ALCL 34 ; crizotinib in ALK1 ALCL 35,36 ; mogamulizumab in ATLL 37 ; HDACi and demethylating agents in AITL or T FH -PTCL 38 ; and possibly enasidenib in IDH2-mutant AITL. 39 Thus, accurate diagnosis may be important for patient treatment and in clinical trials of new drugs.…”

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

“…On the other hand, for translocation events of NPM1, treatment has been associated with the elimination of the fusion protein directly. This includes anaplastic large-cell lymphoma with NPM1-ALK (anaplastic lymphoma kinase) and T-cell lymphoma with NPM1-TYK2 (tyrosine kinase 2) [ 58 , 59 ]. It must be noted that only a small proportion of patients who exhibit NPM1 mutations outside of AML can be found.…”

Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL

“…ALK TKI resistance can either be ALK-dependent or -independent with the former largely occurring due to mutations in ALK ( Figure 1 and Figure 4 ). These have been reported as either mutations in residues at the TKI binding site, or those that result in conformational changes that increase aberrant ALK activity [ 76 , 77 ]. Extensive studies of ALK-dependent resistance mechanisms in NSCLC [ 17 , 78 ] have identified numerous mutations which in some cases are specific to a certain ALK TKI and in others are ubiquitous amongst the ALK TKIs ( Table 1 ).…”