Chronic myelomonocytic leukemia: molecularly contaminated, but not defined

Chronic myelomonocytic leukemia (CMML) is a clonal, hematopoietic stem cell disorder, with overlapping features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).[1] Advances in next-generation sequencing (NGS) technology have defined the mutational landscape in affected patients. Common abnormalities include mutations in epigenetic regulators (TET2 ∼ 60% and ASXL1 ∼ 40%), spliceosome components (SRSF2 ∼ 50%), transcription factors (RUNX1 ∼ 15%), and signal pathways (RAS ∼ 30%).[2,3] Of these, thus far, only clonal ASXL1 mutations have demonstrated an adverse prognostic impact on over-all survival (OS).[2,4] ASXL1 mutations disrupt the polycomb repressor complex (PRC2) and affect tri-methylation of H3K27 (repressive epigenetic mark), resulting in transcriptional activation and gene dysregulation.[3] Patients with CMML present in the seventh decade of life, with symptoms overlapping between MDS-like (effect of low blood counts) and MPN-like (effects of hepatosplenomegaly); with an inherent risk of transformation to acute myeloid leukemia (∼15–30%).[5] The median OS for affected patients is generally <2 years.[1,3]

Similar to MDS and MPN, CMML is also closely associated with inflammation and autoimmune diseases (AID).[6,7] Affected patients tend to have a pro-inflammatory state with cytokine mediated symptoms (fevers, chills night sweats, and fatigue), capillary leak and inflammatory organ involvement (acute lung injury, vasculitis, arthritis, and Sweets syndrome). AID such as Hashimoto’s thyroiditis (HT) and idiopathic thrombocytopenic purpura (ITP) are relatively frequent.[7] In this issue of the journal, Elbaek et al. carry out a case–control study, evaluating chronic inflammatory and AID in 112 patients with CMML and 231 unmatched controls with chronic lymphocytic leukemia (CLL).[8] They observe that 16.1% of CMML subjects and 6.5% of CLL controls presented with a history of chronic inflammatory or AID and that this finding was associated with an increased risk of developing CMML [adjusted OR 3.24, 95% CI 1.5–7.0]. AID evaluated included; rheumatoid arthritis (RA), Sjögren’s syndrome, ITP, primary biliary cirrhosis, inflammatory bowel diseases (IBD), polymyalgia rheumatica (PMR), psoriasis, vitiligo, Graves’ disease and HT. At an individual level, the association with CMML was statistically significant for PMR (p < 0.01) and ITP (p = 0.03). They also observed that in comparison to controls, levels of C-reactive protein (CRP) were increased in CMML cases [0R; 2.16, 95% CI 1.73–2.69]. They justify the use of CLL controls based on the fact that there is no reported negative association between CLL and autoimmunity. They conclude by implying a causal relationship between chronic inflammation/autoimmunity and the subsequent development of CMML.

In a related study on 123 CMML patients, 24 (19.5%) were found to have AID/inflammatory diseases, with four (16%) demonstrating ≥1 condition.[9] They found the prevalence of these conditions in CMML to be similar to that of MDS, but higher than that of the general population (3.2–5%).[6] Similarly, in a large MDS study (n = 1408), 391 patients (28%) were found to have AID, with HT (44%) being most common, followed by ITP (12%) and RA (10%).[7] In this study, AID were associated with a protective effect, with affected patients having a better OS and leukemia-free survival.[7]

The role of the “inflammasome” in MDS/CMML is extensively being explored. The inflammasome is an intracellular protein complex consisting of NRLP3 (nucleotide-binding domain and leucine rich repeat containing family), apoptosis-associated speck protein with a caspase activation and recruitment domain (ASC), and caspase-1.[10] Pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) activate the inflammasome, resulting in activation of caspase-1 and cleavage of pro-interleukin (IL)-1β to form active IL-1β, which leaves the cell and can then bind to the IL-1 receptor, resulting in inflammation.[10] NLRP3 can also be modulated by DAMP signals, such as S100A9, and reactive oxygen species (ROS). A recent study identified a higher frequency of NLRP3 variants (∼15%) in MDS patients with AID. In addition, heterozygous mutations in MEFV, a gene known to be associated with familial Mediterranean fever (pro-inflammatory disease) have been documented in MDS patients with Sweets syndrome.[11]

The lack of prospective evidence makes it difficult to ascertain if AID/chronic inflammatory states truly precede the development of MDS/CMML, or whether they are the result of early onset of clonal disease. Precursor myeloid clones can be detected several months before morphological recognition of MDS/CMML. In addition, patients presenting with AID often do not undergo bone marrow examinations at diagnosis, making it very difficult to answer this question retrospectively. One also has to be careful with the interpretation of data on AID such as ITP, PMR and HT, given their frequent occurrence rates in the general population. Patients with germline mutations in ANKRD26, RUNX1 and ETV6 can present with long standing thrombocytopenia prior to myeloid transformation, and are often misdiagnosed to have ITP.[12] In summary, although CMML is enriched in epigenetic dysregulation and signal pathway abnormalities, the exact pathogenesis of this disease and the higher than expected prevalence of AID/chronic inflammatory states, some of which precede the diagnosis of CMML, remains to be elucidated.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2016.1169411.