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Abstract Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.

Abstract BACKGROUND Mutations in the RAS‐MAPK pathway, such as KRAS, NRAS, and BRAF, are known as high‐risk factors associated with poor prognosis in patients with various cancers, but studies in myeloma have yielded mixed results. METHODS We describe the clinicopathologic, cytogenetic, molecular features, and outcomes of 68 patients with RAS/BRAF‐mutated myeloma, and compare with 79 patients without any mutations. RESULTS We show that KRAS, NRAS, and BRAF were mutated in 16%, 11%, and 5% of cases, respectively. RAS/BRAF‐mutated patients had lower hemoglobin and platelet counts, higher levels of serum lactate dehydrogenase and calcium, higher percentage of bone marrow plasma cells, and more advanced R‐ISS stage. RAS/BRAF mutations were associated with complex karyotype and gain/amplification of CKS1B. The median overall survival and progression‐free survival were significantly shorter for RAS/BRAF‐mutated patients (69.0 vs. 220.7 months, p = 0.0023 and 46.0 vs. 60.6 months, p = 0.0311, respectively). Univariate analysis revealed that KRAS mutation, NRAS mutation, lower hemoglobin, elevated lactate dehydrogenase, higher R‐ISS stage, complex karyotype, gain/amplification of CKS1B, monosomy 13/RB1 deletion and lack of autologous stem cell transplantation were associated with poorer prognosis. Multivariate analysis showed that KRAS mutation, lower hemoglobin level, higher level of serum calcium, higher ISS stage, and lack of autologous stem cell transplantation predict inferior outcome. CONCLUSIONS RAS/BRAF mutations occur in 30%–40% of myeloma cases and are associated with higher tumor burden, higher R‐ISS stage, complex karyotype, and shorter overall survival and progression‐free survival. These findings support testing for RAS/BRAF mutations in myeloma patients and underscore the potential therapeutic benefits of RAS/BRAF inhibitors.

Abstract This report highlights the value of flow cytometry analysis, particularly in the setting of myeloproliferative neoplasms showing features of progression, as neoplastic plasmacytoid dendritic cell (PDC) proliferations may be present, representing either a clonal expansion of mature PDCs related to the underlying myeloproliferative neoplasm or transformation to blastic plasmacytoid dendritic cell neoplasm (BPDCN). BPDCN should always be considered in patients with myeloid neoplasms in progression and/or who develop new cutaneous findings, as it may prompt change of management.

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the patients. PHF6 mutations occurred either concurrently with SF3B1 mutations or in subsequent follow-up samples and are associated with disease progression and impending death in most cases. Most cases had co-mutations, the most common being ASXL1, RUNX1, TET2, and NRAS. With a median follow-up of 39 months (range, 3-155), 17 (81%) patients died, 3 were in complete remission, and 1 had persistent myelodysplastic syndrome. The median overall survival was 51 months. In summary, concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms, with roles as early initiating events and in disease progression, respectively.

Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline “hot spots” are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.

Esophageal schwannoma is a rare tumor first described in 1967 by Chaterlin and Fissore. These tumors are most commonly found incidentally or from diagnostic work up of dysphagia or dyspnea. This entity cannot be diagnosed on clinical or radiographic basis alone. Histology demonstrates palisading spindle cells, few if any mitotic figures, and a peripheral cuff of lymphoid cells. Immunohistochemically, tumor cells stain positive for S100, a characteristic marker of Schwann cells. Once diagnosed, surgical enucleation is the typical treatment method employed.