Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

Abstract

Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC.

Engaging chromatin: PRC2 structure meets function

“…1c), and mutations of the hydrophobic residues involved in this structure (F665C/L/S, F667L, Y726C/D/N/ H and Y728H) are mostly found in myeloid malignancies, mainly in acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and myelodysplastic syndrome (MDS). [109][110][111][112][113][114][115][116] Disruption of one of these residues could result in impaired substrate recognition and, possibly, loss of methyltransferase activity, as demonstrated for the Y726D mutant. 113 The R685 residue, which lies just below the bottom of the hydrophobic pocket, seems to be essential for the correct orientation of F665, and its mutation to cytosine abolishes methyltransferase activity in vitro.…”

Clonal Hematopoiesis with Oncogenic Potential (CHOP): Separation from CHIP and Roads to AML

“…Genetic lesions that are typically detectable in CMML include mutations in SRSF2 (about 50% of patients), TET2 (50–60%), and ASXL1 (35–49%) (Table 1). Mutations associated with disease progression to sAML include mutations in CBL , NRAS, KRAS , RUNX1, and SETBP1 [55,78,79,80,81,82]. These mutations are detectable in at least 10% of all patients with CMML and are associated with poor prognoses.…”

Oligomonocytic chronic myelomonocytic leukemia (chronic myelomonocytic leukemia without absolute monocytosis) displays a similar clinicopathologic and mutational profile to classical chronic myelomonocytic leukemia

“…In addition, the presence of NRAS, RUNX1, SETBP1 or ASXL1 mutations in chronic myelomonocytic leukemia is associated with a more aggressive course independent of the cytogenetic abnormalities. 8,[12][13][14][15] We have encountered occasional cases of myeloid neoplasms showing increased peripheral blood monocytes (≥0.5 × 10 9 /l) and relative monocytosis (≥10%), but not at the level of absolute monocytosis required by the WHO classification. A subset of these cases also had increased bone marrow monocytes.…”