RUNX1 is mutated in ∼10% of adult acute myeloid leukemia (AML). Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal-dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM); ∼44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline vs acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these patients with RUNX1 germline–mutated AML. Moreover, 2 patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations, with variable AML disease onset at 59 and 27 years, respectively. Together, these data suggest a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlight the importance of testing for RUNX1 mutations in instances in which allogeneic stem cell transplantation using a related donor is envisioned.

Aside from the cell-intrinsic factors such as genetic alterations, immune dysregulation in the bone marrow (BM) microenvironment plays a role in the development and progression of myelodysplastic syndromes (MDS). However, the prognostic implications of various immune cells in MDS patients remain unclear. We adopted CIBERSORTx to estimate the relative fractions of 22 subtypes of immune cells in the BM of 316 MDS patients and correlated the results with clinical outcomes. A lower fraction of unpolarized M0 macrophages and higher fractions of M2 macrophages and eosinophils were significantly associated with inferior survival. An immune cell scoring system (ICSS) was constructed based on the proportion of these three immune cells in the BM. The ICSS high-risk patients had higher BM blast counts, higher frequencies of poor-risk cytogenetics, and NPM1, TP53, and WT1 mutations than intermediate- and low-risk patients. The ICSS could stratify MDS patients into three risk groups with distinct leukemia-free survival and overall survival among the total cohort and in the subgroups of patients with lower and higher disease risk based on the revised International Prognostic Scoring System (IPSS-R). The prognostic significance of ICSS was also validated in another independent cohort. Multivariable analysis revealed that ICSS independently predicted prognosis, irrespective of age, IPSS-R, and mutation status. Bioinformatic analysis demonstrated a significant correlation between high-risk ICSS and nuclear factor kappa B signaling, oxidative stress, and leukemic stem cell signature pathways. Further studies investigating the mechanistic insight into the crosstalk between stem cells and immune cells are warranted.

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Key Points• Through lncRNA profiling, we identified an MDS patient subset with distinct clinical and mutational patterns along with inferior outcomes.• A concise yet powerful 4-lncRNA risk-scoring system was devised with the potential to improve current MDS risk stratification.Long noncoding RNAs (lncRNAs) not only participate in normal hematopoiesis but also contribute to the pathogenesis of acute leukemia. However, their clinical and prognostic relevance in myelodysplastic syndromes (MDSs) remains unclear to date. In this study, we profiled lncRNA expressions in 176 adult patients with primary MDS, and identified 4 lncRNAs whose expression levels were significantly associated with overall survival (OS). We then constructed a risk-scoring system with the weighted sum of these 4 lncRNAs. Higher lncRNA scores were associated with higher marrow blast percentages, higher-risk subtypes of MDSs (based on both the Revised International Prognostic Scoring System [IPSS-R] and WorldHealth Organization classification), complex cytogenetic changes, and mutations in RUNX1, ASXL1, TP53, SRSF2, and ZRSR2, whereas they were inversely correlated with SF3B1 mutation. Patients with higher lncRNA scores had a significantly shorter OS and a higher 5-year leukemic transformation rate compared with those with lower scores. The prognostic significance of our 4-lncRNA risk score could be validated in an independent MDS cohort. In multivariate analysis, higher lncRNA scores remained an independent unfavorable risk factor for OS (relative risk, 4.783; P , .001) irrespective of age, cytogenetics, IPSS-R, and gene mutations. To our knowledge, this is the first report to provide a lncRNA platform for risk stratification of MDS patients. In conclusion, our integrated 4-lncRNA risk-scoring system is correlated with distinctive clinical and biological features in MDS patients, and serves as an independent prognostic factor for survival and leukemic transformation. This concise yet powerful lncRNA-based scoring system holds the potential to improve the current risk stratification of MDS patients.

Myelodysplastic syndrome (MDS) comprised a heterogeneous group of diseases. The prognosis of patients varies even in the same risk groups. Searching for novel prognostic markers is warranted. Leukemic stem cells (LSCs) are responsible for chemoresistance and relapse in leukemia. Recently, expressions of 17 genes related to stemness of LSCs were found to be associated with prognosis in acute myeloid leukemia patients. However, the clinical impact of LSC genes expressions in MDS, a disorder arising from hematopoietic stem cells, remains unclear. We analyzed expression profile of the 17 stemness-related genes in primary MDS patients and identified expression of 4 genes (LAPTM4B, NGFRAP1, EMP1, and CPXM1) were significantly correlated with overall survival (OS). We constructed an LSC4 scoring system based on the weighted sums of the expression of 4 genes and explored its clinical implications in MDS patients. Higher LSC4 scores were associated with higher revised International Prognostic Scoring System (IPSS-R) scores, complex cytogenetics, and mutations in RUNX1, ASXL1, and TP53. High-score patients had significantly shorter OS and leukemia-free survival (LFS), which was also confirmed in 2 independent validation cohorts. Subgroup analysis revealed the prognostic significance of LSC4 scores for OS remained valid across IPSS-R lower- and higher-risk groups. Furthermore, higher LSC4 score was an independent adverse risk factor for OS and LFS in multivariate analysis. In summary, LSC4 score can independently predict prognosis in MDS patients irrespective of IPSS-R risks and may be used to guide the treatment of MDS patients, especially lower-risk group in whom usually only supportive treatment is given.