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Editorials
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Some ARCH-related mutations can increase the risk for leukemia,12 while others possibly increase the risk for heart disease and diabetes.13 From a pathogenetic stand- point, the study of Agathangelidis et al.1 provides the proof of principle that ARCH may also associate with expansion of B-cell clones with CLL phenotype, and con- nects ARCH with MBL and CLL in a continuum of evolu- tion from HSCP clones to mature B-cell clones (Figure 1), thus validating in vivo in patients the notion initially reported from mice studies that the propensity to gener- ate clonal B cells has already been acquired at the HSCP stage.14 To robustly establish this association and to gain greater insight into the pathogenetics, larger cohorts of MBL and CLL patients should be investigated with the rigorous approach utilized by Agathangelidis et al.1
One of the long-term complications of chemoim- munotherapy in CLL is the development of treatment- related MDS/AML.15 Chemoimmunotherapy poses a strong selection bottleneck to HSCPs, and thus only the fittest HSCPs survive and repopulate after the stress of chemoimmunotherapy.16 HSCP fitness may be sustained by somatic mutations in the context of a preceding ARCH, and it is increasingly recognized as a risk factor for therapy-related MDS/AML.17 Among elderly patients who receive chemotherapy and develop therapy-related MDS/AML, most have ARCH before chemotherapy. Consistently, ARCH associates with an increased rate of therapy-related AML/MDS.17 Following this line of evi- dence, the study by Agathangelidis et al.1 prompts inves- tigation into whether the finding of an ARCH in CLL patients who receive chemoimmunotherapy is a risk fac- tor for the development of therapy-related MDS/AML. If this is proved to be the case, given the availability of novel agents for the treatment of CLL that are not stress- ful for HSCP, ARCH might become a new biomarker for tailoring treatment in CLL.
References
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