The classical nature of distinctive CMML monocytes

In this issue of Blood, Talati et al use multiparameter flow cytometry to immunophenotypically characterize peripheral blood cells of patients with chronic myelomonocytic leukemia (CMML) as being comprised of a quantitatively increased subset of the disease's hallmark cells, the classical monocytes.¹  This finding provides an additive marker for establishing the diagnosis of this disorder as being a myeloid clonal hemopathy with a spectrum of abnormal proliferative and differentiative clinical features.

CMML is a myeloid clonal stem cell disorder associated with peripheral blood monocytosis and an inherent tendency to transform into acute myeloid leukemia that has been classified as being within the binary nosologic myelodysplastic syndromes (MDS)/myeloproliferative neoplasm category.²  As such, these patients have varying degrees of defective hematopoietic cell differentiation and proliferation that generate the major clinical features related to either marrow failure or constitutional symptoms and organomegaly associated with excessive myeloproliferation. Uncertainty persists regarding whether these illnesses with high or low blood counts plus monocytosis represent a continuum on a spectrum of a clonal disease or are rather separate disorders with related clinical features. Additionally, distinguishing clonal causes of monocytosis from those reactive to inflammatory or infectious disorders may be problematic.

Clonal cytogenetic changes are seen in ∼30% of CMML patients, and recurrent somatic mutations are present in >90%, especially the prevalent spliceosome mutations and those involved with epigenetic regulation.^3,4  A number of prognostic systems using different clinical parameters have been developed for CMML, and all were found to be valid, with some demonstrating ASXL1 gene mutations either alone or with additional mutations having additive adverse prognostic risk impact.^5,6  These data suggest that combinations of clinical and molecular information will improve the accuracy of current CMML prognostic systems and biological understanding.

Monocytes have been separated into classical, intermediate, and nonclassical subsets by their specific immunophenotyic characteristics (CD14⁺CD16^–, CD14⁺CD16⁺, and CD14^–CD16⁺, respectively).⁷  In this issue of Blood, Talati et al provide a short report with data indicating the qualitative and quantitative difference of CMML monocytes compared with such cells from reactive conditions. For this, they validated a multiparameter flow cytometry assay, proposed by Selimoglu-Buet et al,⁸  evaluating the relative proportions of the standard monocytic markers CD14 and CD16 on these cells. Reproducibly, these studies demonstrated CMML to be distinctive by having ≥94% of these monocytes being classical in type. These immunophenotypic features persisted in patients having the differentiative and proliferative types of CMML and for those in lower and higher adverse clinical risk categories (ie, CMML-0, -1 or -2; ie, patients with marrow blasts <5%, 5% to 9%, or 10% to 19%). This characteristic monocytic phenotype is demonstrative of defective cellular differentiation. Treatment did not alter these features in this study, although such was not the case in the earlier report by Selimoglu-Buet.⁸  These findings indicate that CMML represents a continuum on the spectrum of a neoplastic disorder. However, it will be of importance to determine the association of classical monocytes with the known aberrant antigenic phenotypes of CMML monocytes, such as overexpression of CD56, aberrant expression of CD2, or decreased expression of HLA-DR, CD13, CD11c, CD15, CD64, or CD36.

The 3 distinguishable monocyte subsets represent distinct stages of monocyte differentiation that depend on macrophage colony-stimulating factor (M-CSF) signals via the M-CSF receptor (CD115) and possess disparate functional features. Upon stimulation with LPS, classical monocytes produce the highest levels and broadest range of cytokines that include granulocyte colony stimulating factor, IL-10, CCL2, IL-6, and S100 inflammatory proteins.⁹  Expansion of the nonclassical monocytes occurs mostly in infection or inflammatory conditions, and this subset is generally considered to be proinflammatory monocytes and to produce comparatively higher levels of TNF-α and IL-1β. In contrast, intermediate monocytes produce these cytokines at significantly lower levels, but express high levels of major histocompatibility complex class II processing and presentation genes. Recent transcriptomic analyses provide effective characterization of the expression of potential key regulatory genes in subsets of human monocytes.¹⁰  Evaluation of cell proliferation–related signaling pathways have shown the enhanced sensitivity of CMML monocytes and other cells to granulocyte-macrophage–CSF.

Classical and intermediate monocytes are recruited into different tissues through the chemokine C-C receptor 2, whereas this occurs via the chemokine CX3C receptor 1 for nonclassical monocytes. Such features may explain the differing sites of tissue localization of CMML monocytes associated with disease progression.

Extending their studies to MDS, Telati et al also reported that classical monocytosis was present in 28% of these patients, although this finding was not shown in an earlier study.⁸  These patients were generally in the lower risk Revised International Prognostic Scoring System categories and had a trend toward improved survival. Thus, although capable of separating clonal from reactive monocytes, future investigations are required to determine whether this immunophenotypically defined monocyte subset (ie, ≥ 94% classical monocytes) will clarify the boundary between MDS and CMML.

These and related studies should prove to be additive for analyzing the disparate functions that immunophenotypic and mutationally characterized monocytes possess for clinical and pathogenetic evaluation of the nature of CMML. Further, they will aid diagnosis of this disease as being a myeloid clonal hemopathy with a spectrum of abnormal proliferative and differentiative cellular and clinical features.