Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations

Abstract

Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we performed whole-genome sequencing in 11 individuals with monoclonal B- cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

Age-related clonal hematopoiesis and monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia: a new association?

“…13 From a pathogenetic standpoint, 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 connects ARCH with MBL and CLL in a continuum of evolution 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 generate 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 chemoimmunotherapy in CLL is the development of treatmentrelated 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.…”

“…Consistently, ARCH associates with an increased rate of therapy-related AML/MDS. 17 Following this line of evidence, the study by Agathangelidis et al 1 prompts investigation into whether the finding of an ARCH in CLL patients who receive chemoimmunotherapy is a risk factor 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 stressful for HSCP, ARCH might become a new biomarker for tailoring treatment in CLL.…”

“…While Agathangelidis et al acknowledge these limitations, three major findings characterize their manuscript. 1 First, lowcount MBL, high-count MBL and highly stable CLL share a similar genetic landscape and mutational signatures, which include the presence of mutations in known drivers associated with poor outcome, such as NOTCH1, SF3B1, POT1, [2][3][4] indicating that these mutations are not sufficient to drive the aggressiveness of the disease by themselves. Second, the mutational landscape of paired PMN suggests that most of these patients carry a clonal hematopoiesis that could possibly be age-related.…”

Update on Lymphoma classification: The 2016 revised World Health Organization Classification of Hematopoietic and Lymphoid Neoplasms

“…The concept of monoclonal B‐cell lymphocytosis, as a precursor of all cases of overt CLL/SLL, has now been expanded and there are two subtypes: “low‐count” (<0.5 × 10 9 /L monoclonal B cells) with very low, if at all, risk of progression to overt CLL/SLL and “high‐count” (≥0.5 × 10 9 /L and <5.0 × 10 9 /L of monoclonal B cells) with a significantly higher risk of progression to overt CLL/SLL . The genomic landscape of MBL and stable CLL/SLL is highly similar showing a low frequency of driver mutations …”