Summary Myeloid malignancies, including acute myeloid leukemia (AML), arise from the expansion of hematopoietic stem/progenitor cells which acquire somatic mutations. Bulk molecular profiling suggests step-wise mutation acquisition, where mutant genes with high variant allele frequencies (VAFs) occur early in leukemogenesis and mutations with lower VAFs are thought to be acquired later 1 – 3 . Although bulk sequencing informs leukemia biology and prognostication, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate mutational order. To delineate the clonal framework of myeloid malignancies, we performed single cell mutational profiling on 146 samples from 123 patients. We found AML is dominated by a small number of clones, which frequently harbor co-occurring mutations in epigenetic regulators. Conversely, mutations in signaling genes often occur more than once in distinct subclones consistent with increasing clonal diversity. We next mapped clonal trajectories for each sample and uncovered mutation combinations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our studies of single cell clonal architecture provides novel insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
• Recurrent hypomorphic cohesin defects and cohesin low expression were identified in a significant proportion of patients with MDS and AML.• Cohesin mutations likely represent secondary events in clonal hierarchy and contribute to clonal transformation.Somatic cohesin mutations have been reported in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). To account for the morphologic and cytogenetic diversity of these neoplasms, a well-annotated cohort of 1060 patients with myeloid malignancies including MDS (n 5 386), myeloproliferative neoplasms (MPNs) (n 5 55), MDS/MPNs (n 5 169), and AML (n 5 450) were analyzed for cohesin gene mutational status, gene expression, and therapeutic and survival outcomes. Somatic cohesin defects were detected in 12% of patients with myeloid malignancies, whereas low expression of these genes was present in an additional 15% of patients. Mutations of cohesin genes were mutually exclusive and mostly resulted in predicted loss of function. Patients with low cohesin gene expression showed similar expression signatures as those with somatic cohesin mutations. Cross-sectional deepsequencing analysis for clonal hierarchy demonstrated STAG2, SMC3, and RAD21 mutations to be ancestral in 18%, 18%, and 47% of cases, respectively, and each expanded to clonal dominance concordant with disease transformation. Cohesin mutations were significantly associated with RUNX1, Ras-family oncogenes, and BCOR and ASXL1 mutations and were most prevalent in high-risk MDS and secondary AML. Cohesin defects were associated with poor overall survival (27.2 vs 40 months; P 5 .023), especially in STAG2 mutant MDS patients surviving >12 months (median survival 35 vs 50 months; P 5 .017). (Blood.
Mutations in genes involved in DNA methylation (DNAme; e.g., TET2, DNMT3A) , are frequently observed in hematological malignancies 1 – 3 and clonal hematopoiesis 4 , 5 . Applying single-cell sequencing to murine hematopoietic stem and progenitor cells, we observed that these mutations disrupt hematopoietic differentiation, causing opposite shifts in the frequencies of erythroid vs. myelo-monocytic progenitors upon Tet2 or Dnmt3a loss. Notably, these shifts trace back to transcriptional priming skews in uncommitted hematopoietic stem cells (HSCs). To reconcile genome-wide DNAme changes with specific erythroid vs. myelo-monocytic skews, we provide evidence in support of differential sensitivity of transcription factors due to biases in CpG enrichment in their binding motif. Single-cell transcriptomes with targeted genotyping showed similar skews in transcriptional priming of DNMT3A -mutated human clonal hematopoiesis bone marrow progenitors. These data show that DNAme shapes the hematopoietic differentiation topography, and support a model in which genome-wide methylation changes are transduced to differentiation skews through biases in transcription factor binding-motif CpG enrichment.
Incidence. Cancer occurring between the ages of 15 and 30 years is 2.7 times more common than cancer occurring during the first 15 years of life, yet is much less common than cancer in older age groups, and accounts for just 2% of all invasive cancer. Cancer in adolescents and young adults is unique in the distribution of the types that occur. Hodgkin lymphoma, melanoma, testis cancer, female genital tract malignancies, thyroid cancer, soft-tissue sarcomas, non-Hodgkin lymphoma, leukemia, brain and spinal cord tumors, breast cancer, bone sarcomas, and nongonadal germ cell tumors account for 95% of the cancers in this age group. The frequency distribution of cancer types changes dramatically from age 15-30, such that the pattern at the youngest age does not resemble the one at the oldest. The incidence of cancer in this age group increased steadily during the past quarter century. This increase is declining and at the older end of the age range appears to be returning to the incidence of the 1970s. Males in the 15-to 29-year age group have been at higher risk of developing cancer, with the risk directly proportional to age. Non-Hispanic whites have had the highest risk of developing cancer during this phase of life, and Asians, American Indians and Native Alaskans the lowest. Males had a worse prognosis than females. African-Americans, American Indian/Alaska Natives had a worse prognosis than white non-Hispanics and Asians.Mortality & Survival. At the beginning of the last quarter century, the diagnosis of cancer in 15-to 29-year-olds carried a more favorable prognosis, on the average, relative to cancer at other ages. Since then, there has been a lack of progress in survival improvement among older adolescents and young adults relative to all other ages. Survival improvement trends portend a worse prognosis for young adults diagnosed with cancer today than 25 years ago. The survival deficit is increasing with longer follow-up of the survivors, and is worse in males. Among 15-to 29-year-olds, non- Learning ObjectivesAfter completing this course, the reader will be able to:1. Define the cancers most common in 15-to 29-year-olds.2. Identify the variations in cancer histology in this age group according to age, sex, and race/ethnicity.3. Understand survival trend differences during the past quarter century.4. Perceive incidence and survival according to sex, race/ethnicity, and age groups.5. Discuss areas where progress has been suboptimal in managing cancer in 15-to 29-year-olds.Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S. Copyright law.Unauthorized reproduction is prohibited. Risk Factors. In general, there are relatively scant data to support either an environmental causation or an inherited predisposition to cancer in this age group. The majority of cases of cancer occurring before age 30 appear to be spontaneous and unrelated to either carcinogens in the environment or family cancer syndromes. Overall, fam...
Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.
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