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The mutational landscape in patients with MDS/CMML and systemic inflammatory and autoimmune diseases

Feb 16, 2021

Up to a fifth of patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) also have a diagnosis of systemic inflammatory and autoimmune diseases (SIAD). While it is thought that T cells may play a role here, the pathophysiological mechanisms underlying this association remain undetermined with limited genetic data available.

At the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Lin-Pierre Zhao presented novel data from a retrospective study examining the mutational landscape in patients with MDS/CMML and SIAD and its effect on CD8+ T cell repertoire.1 The key points of the study are summarized below.

Study design1

This retrospective study was performed at the Clinical Department of Hematology, Hôpital Saint-Louis, Paris, FR, between January 2012 and December 2017. Overall, 404 patients with MDS and CMML were included, 85 of which had a concurrent diagnosis of SIAD. The control cohort included 319 patients who did not have SIAD. Patients were followed up for a median of 32.2 months.


Patient baseline characteristics are shown in Table 1. The number of patients with CMML was similar between cohorts, and cohorts were also comparable with regards to age and MDS/CMML subtype. There was no significant difference in median overall survival (p = 0.97) or in median progression-free survival (p = 0.84) between the SIAD and control cohorts.

Table 1. Patient characteristics (adapted from Zhao et al.1)

ANC, absolute neutrophil count; CMML, chronic myelomonocytic leukemia; MDS, myelodysplastic syndromes; IPSS-R, International Prognostic Scoring System-Revised; SIAD, systemic inflammatory and autoimmune diseases; WBC, white blood cell.
*Statistical significance is indicated in bold.


SIAD patients
(n = 85)

Control patients
 (n = 319)

p value*

Median age at MDS/CMML diagnosis, years (range)

71.4 (66.0–80.7)

72.5 (65.5–79.1)

Females, %



Peripheral blood counts at diagnosis
Hemoglobin, g/dL (range)
g/L (range)
              WBC, g/L (range)
              ANC, g/L (range)
              Monocytes, g/L (range)

10.6 (9.1–12.3)
116 (67–219)
5.3 (3.2–8.1)
3.4 (1.7–5.2)
0.39 (0.21–0.80)

10.6 (9.0–12.2)
132 (63–234)
5.9 (2.9–6.7)
3.2 (1.3–3.9)
0.61 (0.25–0.94)


Mean marrow blasts, %



< 0.01

IPSS-R risk category, %




Complex/monosomal karyotype, %



SIAD diagnosis, %
              Inflammatory arthritis
              Systemic vasculitis
              Autoimmune cytopenia
              Connective tissue disease
              Neutrophilic dermatosis
              Inflammatory bowel disease


Mutational analysis/landscape

Both cohorts had a median of two mutations (range, 1–4). Mutations in the TET2 and IDH genes, which are involved in the same methylation pathway, and those in SRSF2 were significantly more frequent in patients with SIAD than control patients (Table 2). Furthermore, SRSF2 mutations were correlated with the presence of TET2 and IDH mutations in the SIAD cohort (p < 0.01) and the control cohort (p < 0.01). The frequency of mutations in other epigenetic regulators, splicing factors, signaling and transcription genes were comparable between cohorts.

Table 2. Comparison of the frequency of mutations between SIAD and control cohorts1

SIAD, systemic inflammatory and autoimmune diseases.

Mutation, %

SIAD cohort
(n = 85)

Control cohort
 (n = 319)

p value








< 0.01




< 0.01




< 0.01

Univariate analysis showed an association between TET2, IDH1/2, and SRSF2 mutations with SIAD. Furthermore, multivariate regression analysis revealed that the proportion of marrow blasts (odds ratio [OR], 0.86; 95% CI, 0.78–0.93; p < 0.01), TET2/IDH mutations (OR, 1.87; 95% CI, 1.08–3.20; p = 0.02), and SRSF2 mutations (OR, 2.21; 95% CI, 1.14–4.28; p = 0.02) were independently associated with SIAD.

Immunological analysis

Flow cytometry was performed on T cells from 17 patients with TET2/IDH mutations and 11 TET2/IDH wild type patients. Mutations in TET2/IDH were associated with decreased levels of stem (p = 0.02), central (p < 0.01), and transitional (p = 0.01) memory T cells when compared to TET2/IDH wild type samples. The proportion of CD8+ T cells expressing CD96, an immune checkpoint receptor involved in T cell regulation, was significantly lower in patients with TET2/IDH mutations (48.8%) compared to wild type patients (71.1%; p < 0.05). Unsupervised analysis using the Citrus algorithm confirmed that CD96+ central memory T cells are reduced in patients with TET2/IDH mutations. No association of SRSF2 mutations with dysregulation of T cell homeostasis or CD96 expression was found.


This retrospective study found that mutations in TET2, IDH1/2, and SRSF2 genes were associated with SIAD in patients with MDS/CMML. Moreover, only TET2 and IDH mutations were associated with dysregulated immune T cell homeostasis. The authors proposed that these mutations may induce both MDS/CMML and systemic inflammation. However, further studies are required to uncover the precise mutational landscape in patients with MDS/CMML and concurrent SIAD, and to further understand the underlying mechanisms of T cell imbalance.

  1. Zhao L-P, Boy M, Azoulay C, et al. MDS/CMML with TET2 or IDH mutation are associated with systemic inflammatory and autoimmune diseases (SIAD) and T cell dysregulation. 2020;136(suppl. 1):31-32. DOI: 10.1182/blood-2020-141228