Page 19 - Haematologica-5

Editorials
Age-related clonal hematopoiesis and monoclonal B-cell lymphocytosis / chronic lymphocytic leukemia: a new association?
Adalgisa Condoluci and Davide Rossi
Hematology, Institute of Oncology Research, and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
E-mail: davide.rossi@eoc.ch doi:10.3324/haematol.2018.191098
Agathangelidis et al.1 compared the mutational land- scape of low-count monoclonal B-cell lymphocyto- sis (MBL), high-count MBL and highly stable chron- ic lymphocytic leukemia (CLL) with confirmed lack of pro- gression after a very long follow up (>10 years). The Authors also studied the polymorphonuclear (PMN) frac- tion and germline DNA from buccal swabs of the same individuals. Whole genome sequencing was complement- ed with deep sequencing of targeted genes.
The sample size, along with the low coverage imposed by whole genome sequencing, are both limitations in efforts to discover yet unknown variants that might actu- ally be recurrent in these conditions. While Agathangelidis et al. acknowledge these limitations, three major findings characterize their manuscript.1 First, low- count MBL, high-count MBL and highly stable CLL share a similar genetic landscape and mutational signatures, which include the presence of mutations in known driv- ers associated with poor outcome, such as NOTCH1, SF3B1, POT1,2-4 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. Third, a number of somatic mutations were found in both the MBL/CLL cells and PMN, supporting the idea that the MBL/CLL clone stemmed from a common ancestral
hematopoietic precursor that was able to participate in both lymphoid and myeloid differentiation. By docu- menting that the DNA from PMN was free from contam- ination by MBL/CLL DNA, for example, by using molec- ular minimal residual disease methods relying on the individual patient’s specific immunoglobulin gene rearrangements, the Authors have provided further evi- dence of this important finding which, although previ- ously reported,5,6 had remained a subject of debate.
Several hematologic malignancies, including CLL, mul- tiple myeloma (MM) and acute myeloid leukemia (AML), have well-defined precursor states that precede the devel- opment of overt cancer. CLL is always preceded by a high MBL count,7 MM is almost always preceded by mono- clonal gammopathy of undetermined significance (MGUS),8 and at least a quarter of all patients with myelodysplastic syndromes (MDS) have disease that evolves into AML.9 Deep genomic sequencing of normal subjects revealed that during human aging, the expansion of 1 or more hematopoietic stem and progenitor cells (HSPC) will result in clones that will sustainably con- tribute more than others to the production of mature blood cells. Accordingly, age-related clonal hematopoiesis (ARCH) is defined as the expansion of HSPC clones, har- boring specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematologic malignancies.10 MDS are frequently preceded by ARCH.11
Figure 1. Hypothetical model of evolution from age-related clonal hematopoiesis to monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia.
haematologica | 2018; 103(5)
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