Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease.

PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

COVID-19 outcomes in persons with hemophilia: results from a US-based national COVID-19 surveillance registry.

BACKGROUND: Hypercoagulable state contributing to thrombotic complications worsens COVID-19 severity and outcomes, whereas anticoagulation improves outcomes by alleviating hypercoagulability. OBJECTIVES: To examine whether hemophilia, an inherent hypocoagulable condition, offers protection against COVID-19 severity and reduces venous thromboembolism (VTE) risk in persons with hemophilia (PwH). METHODS: A 1:3 propensity score-matched retrospective cohort study used national COVID-19 registry data (January 2020 through January 2022) to compare outcomes between 300 male PwH and 900 matched controls without hemophilia. RESULTS: Analyses of PwH demonstrated that known risk factors (older age, heart failure, hypertension, cancer/malignancy, dementia, and renal and liver disease) contributed to severe COVID-19 and/or 30-day all-cause mortality. Non-central nervous system bleeding was an additional risk factor for poor outcomes in PwH. Odds of developing VTE with COVID-19 in PwH were associated with pre-COVID VTE diagnosis (odds ratio [OR], 51.9; 95% CI, 12.8-266; p < .001), anticoagulation therapy (OR, 12.7; 95% CI, 3.01-48.6; p < .001), and pulmonary disease (OR, 16.1; 95% CI, 10.4-25.4; p < .001). Thirty-day all-cause mortality (OR, 1.27; 95% CI, 0.75-2.11; p = .3) and VTE events (OR, 1.32; 95% CI, 0.64-2.73; p = .4) were not significantly different between the matched cohorts; however, hospitalizations (OR, 1.58; 95% CI, 1.20-2.10; p = .001) and non-central nervous system bleeding events (OR, 4.78; 95% CI, 2.98-7.48; p < .001) were increased in PwH. In multivariate analyses, hemophilia did not reduce adverse outcomes (OR, 1.32; 95% CI, 0.74-2.31; p = .2) or VTE (OR, 1.14; 95% CI, 0.44-2.67; p = .8) but increased bleeding risk (OR, 4.70; 95% CI, 2.98-7.48; p < .001). CONCLUSION: After adjusting for patient characteristics/comorbidities, hemophilia increased bleeding risk with COVID-19 but did not protect against severe disease and VTE.

Genomic analysis of venous thrombosis in children with acute lymphoblastic leukemia from diverse ancestries.

Venous thrombosis is a common adverse effect of modern therapy for acute lymphoblastic leukemia (ALL). Prior studies to identify risks of thrombosis in pediatric ALL have been limited by genetic screens of pre-identified genetic variants or genome- wide association studies (GWAS) in ancestrally uniform populations. To address this, we performed a retrospective cohort evaluation of thrombosis risk in 1,005 children treated for newly diagnosed ALL. Genetic risk factors were comprehensively evaluated from genome-wide single nucleotide polymorphism (SNP) arrays and were evaluated using Cox regression adjusting for identified clinical risk factors and genetic ancestry. The cumulative incidence of thrombosis was 7.8%. In multivariate analysis, older age, T-lineage ALL, and non-O blood group were associated with increased thrombosis while non-low-risk treatment and higher presenting white blood cell count trended toward increased thrombosis. No SNP reached genome-wide significance. The SNP most strongly associated with thrombosis was rs2874964 near RFXAP (G risk allele; P=4x10-7; hazard ratio [HR] =2.8). In patients of non-European ancestry, rs55689276 near the α globin cluster (P=1.28x10-6; HR=27) was most strongly associated with thrombosis. Among GWAS catalogue SNP reported to be associated with thrombosis, rs2519093 (T risk allele, P=4.8x10-4; HR=2.1), an intronic variant in ABO, was most strongly associated with risk in this cohort. Classic thrombophilia risks were not associated with thrombosis. Our study confirms known clinical risk features associated with thrombosis risk in children with ALL. In this ancestrally diverse cohort, genetic risks linked to thrombosis risk aggregated in erythrocyte-related SNP, suggesting the critical role of this tissue in thrombosis risk.

Where have all the platelets gone? HIT, DIC, or something else?

Thrombocytopenia in ill children is common; accurately diagnosing the underlying etiology is challenging and essential for appropriate management. Triggers for accelerated consumption of platelets are numerous; common downstream mechanisms of clearance include platelet trapping in microvascular thrombi, phagocytosis, and platelet activation. Thrombocytopenia with microangiopathic hemolytic anemia (MAHA) is frequently due to disseminated intravascular coagulation. Thrombotic microangiopathy (TMA) is a subgroup of MAHA. Specific TMA syndromes include thrombotic thrombocytopenic purpura, complement-mediated TMA (CM-TMA), and Shiga toxin-mediated hemolytic uremic syndrome. Isolated thrombocytopenia is characteristic of immune thrombocytopenia; however, concomitant cytopenias are frequent in critically ill patients, making the diagnosis difficult. Immune thrombocytopenia with large vessel thrombosis is a feature of heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. In addition, thrombocytopenia is common with macrophage activation, which is characteristic of hemophagocytic lymphohistiocytosis. While thrombocytopenia in ill patients can be driven by hypoproliferative processes such as myelosuppression and/or bone marrow failure, this review will focus on consumptive thrombocytopenia due to immune and nonimmune causes.

Common data model for sickle cell disease surveillance: considerations and implications.

Objective: Population-level data on sickle cell disease (SCD) are sparse in the United States. The Centers for Disease Control and Prevention (CDC) is addressing the need for SCD surveillance through state-level Sickle Cell Data Collection Programs (SCDC). The SCDC developed a pilot common informatics infrastructure to standardize processes across states. Materials and Methods: We describe the process for establishing and maintaining the proposed common informatics infrastructure for a rare disease, starting with a common data model and identify key data elements for public health SCD reporting. Results: The proposed model is constructed to allow pooling of table shells across states for comparison. Core Surveillance Data reports are compiled based on aggregate data provided by states to CDC annually. Discussion and Conclusion: We successfully implemented a pilot SCDC common informatics infrastructure to strengthen our distributed data network and provide a blueprint for similar initiatives in other rare diseases.

Clinical characteristics and outcomes of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis managed with different cytoreductive methods.

BACKGROUND: Hyperleukocytosis in patients with acute myeloid leukemia (AML) has been associated with worse outcomes. For cytoreduction, leukapheresis has been used but its clinical utility is unknown, and low-dose cytarabine (LD-cytarabine) is used as an alternative method. METHODS: Children with newly diagnosed AML treated between 1997 and 2017 in institutional protocols were studied. Hyperleukocytosis was defined as a leukocyte count of ≥100 × 109 /L at diagnosis. Clinical characteristics, early complications, survival data, and effects of cytoreductive methods were reviewed. Among 324 children with newly diagnosed AML, 49 (15.1%) presented with hyperleukocytosis. Initial management of hyperleukocytosis included leukapheresis or exchange transfusion (n = 16, considered as one group), LD-cytarabine (n = 18), hydroxyurea (n = 1), and no leukoreduction (n = 14). RESULTS: Compared with patients who received leukapheresis, the percentage decrease in leukocyte counts following intervention was greater among those who received LD-cytarabine (48% vs. 75%; p = .02), with longer median time from diagnosis to initiation of protocol therapy (28.1 vs. 95.2 hours; p < .001). The incidence of infection was higher in patients (38%) who had leukapheresis than those who receive LD-cytarabine (0%) or leukoreduction with protocol therapy (14%) (p = .008). No differences were noted in the outcomes among the intervention groups. Although patients with hyperleukocytosis had higher incidences of pulmonary and metabolic complications than did those without, no early deaths occurred, and the complete remission, event-free survival, overall survival rates, and outcomes of both groups were similar. CONCLUSION: LD-cytarabine treatment appears to be a safe and effective means of cytoreduction for children with AML and hyperleukocytosis.

Incorporating G6PD genotyping to identify patients with G6PD deficiency.

Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is a common X-linked enzyme disorder associated with hemolytic anemia after exposure to fava beans or certain medications. Activity testing is the gold standard for detecting G6PD deficiency; however, this test is affected by various hematologic parameters. Clinical G6PD genotyping is now included in pharmacogenetic arrays and clinical sequencing efforts and may be reconciled with activity results. Patients (n = 1391) enrolled on an institutional pharmacogenetic testing protocol underwent clinical G6PD genotyping for 164 G6PD variants. An algorithm accounting for known interferences with the activity assay is proposed. We developed clinical decision support alerts to inform prescribers when high-risk medications were prescribed, warning of gene-drug interactions and recommending therapy alteration. Of 1391 patients with genotype results, 1334 (95.9%) patients were predicted to have normal G6PD activity, 30 (2.1%) were predicted to have variable G6PD activity and 27 (2%) were predicted to have deficient G6PD activity. Of the 417 patients with a normal genotype and an activity result, 415 (99.5%) had a concordant normal G6PD phenotype. Of the 21 patients with a deficient genotype and an activity result, 18 (85.7%) had a concordant deficient activity result. Genotyping reassigned phenotype in five patients with discordant genotype and activity results: three switched from normal to deficient, and two switched from deficient to normal. G6PD activity and genotyping are two independent testing methods that can be used in conjunction to assign a more informed G6PD phenotype than either method alone.

CPX-351 induces remission in newly diagnosed pediatric secondary myeloid malignancies.

Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.

How we approach thrombosis risk in children with COVID-19 infection and MIS-C.

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with coronavirus disease 2019 (COVID-19). While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19-associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Correlates of successful transition in young adults with sickle cell disease.

The transition period from pediatric care to adult care for patients with sickle cell disease (SCD) is associated with increased mortality and morbidity. Identification of risk factors for unsuccessful transition may aid in developing strategies to improve the transition process and health outcomes in this population. We examined factors associated with unsuccessful transition from pediatric to adult care for patients with SCD at the Johns Hopkins Hospital. We found that public insurance and increased hospitalization rates were associated with poor transition to adult care. The findings provide possible areas of intervention.

Factors associated with red blood cell, platelet, and plasma transfusions among inpatient hospitalizations: a nationally representative study in the United States.

BACKGROUND: Demographic and hospital-level factors associated with red blood cell (RBC), plasma, and platelet transfusions in hospitalized patients across the U.S. are not well characterized. METHODS: We conducted a retrospective analysis of the National Inpatient Sample (2014). The unit of analysis was a hospitalization; sampling weights were applied to generate nationally-representative estimates. The primary outcome was having ≥ 1 RBC transfusion procedure; plasma and platelet transfusions were similarly assessed as secondary outcomes. For each component, factors associated with transfusion were measured using adjusted prevalence ratios (adjPR) and 95% confidence intervals (95% CI) estimated by multivariable Poisson regression. RESULTS: The prevalence of RBC, plasma, and platelet transfusion was 5.8%, 0.9%, and 0.7%, respectively. RBC transfusions were associated with older age (≥ 65 vs. < 18 years; adjPR = 1.80; 95% CI = 1.66-1.96), female sex (adjPR = 1.13; 95% CI = 1.12-1.14), minority race/ethnic status, and hospitalizations in rural hospitals compared to urban teaching hospitals. Prevalence of RBC transfusion was lower among hospitalizations in the Midwest compared to the Northeast (adjPR = 0.73; 95% CI = 0.67-0.80). All components were more likely to be transfused in patients with a primary hematologic diagnosis, patients with a higher number of total diagnoses, patients who experienced a higher number of other procedures, and patients who eventually died in the hospital. In contrast to RBC transfusions, prevalence of platelet transfusion was greater in urban teaching hospitals (vs. rural; adjPR = 1.71; 95% CI = 1.49-1.98) and lower in blacks (vs. whites; adjPR = 0.80; 95% CI = 0.76-0.85). CONCLUSIONS: Nationally, there is heterogeneity in factors associated with transfusion between each blood component, including by hospital type and location. This variability presents patient blood management programs with potential opportunities to reduce transfusions.

Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay.

Contrast-enhanced ultrasound (CEUS) is a versatile imaging modality that improves the diagnostic potential of conventional ultrasound. It allows for portable imaging at the bedside. In this paper, we illustrate how CEUS can be used in evaluating several focal lesions in the pediatric population, including liver hemangioma, telangiectasias, splenic hamartomas, and bladder lesions. We describe the ultrasound findings and contrast enhancement patterns associated with these lesions. Findings are correlated with MRI, CT, and/or pathology when available. This paper demonstrates the value of CEUS in improving characterization of many focal lesions in the pediatric population. CONCLUSION: CEUS is a valuable bedside technique for use in the pediatric population to evaluate focal lesions in various organs, and will allow for safe, more efficient diagnostic imaging. What is Known: • CEUS offers many advantages over CT and MRI and is underutilized in the United States. • It is only FDA approved for vesicoureteral reflux and liver in the pediatric population. However, off label uses are well described. What is New: • This pictorial essay describes ultrasound findings and contrast enhancement patterns associated with liver hemangioma, liver telangiectasia, splenic hamartoma, hemorrhagic ovarian cyst, urachal remnant, spinning top urethras, and kaposiform hemangioendothelioma. • We demonstrate the utility of CEUS in expanding the diagnostic potential of conventional ultrasound.

Association of Perioperative Red Blood Cell Transfusions With Venous Thromboembolism in a North American Registry.

Importance: Increasing evidence supports the role of red blood cells (RBCs) in physiological hemostasis and pathologic thrombosis. Red blood cells are commonly transfused in the perioperative period; however, their association with postoperative thrombotic events remains unclear. Objective: To examine the association between perioperative RBC transfusions and postoperative venous thromboembolism (VTE) within 30 days of surgery. Design, Setting, and Participants: This analysis used prospectively collected registry data from the American College of Surgery National Surgical Quality Improvement Program (ACS-NSQIP) database, a validated registry of 525 teaching and nonteaching hospitals in North America. Participants included patients in the ACS-NSQIP registry who underwent a surgical procedure from January 1 through December 31, 2014. Data were analyzed from July 1, 2016, through March 15, 2018. Main Outcomes and Measures: Risk-adjusted odds ratios (aORs) were estimated using multivariable logistic regression. The primary outcome was the development of postoperative VTE (deep venous thrombosis [DVT] and pulmonary embolism [PE]) within 30 days of surgery that warranted therapeutic intervention; DVT and PE were also examined separately as secondary outcomes. Subgroup analyses were performed by surgical subtypes. Propensity score matching was performed for sensitivity analyses. Results: Of 750 937 patients (56.8% women; median age, 58 years; interquartile range, 44-69 years), 47 410 (6.3%) received at least 1 perioperative RBC transfusion. Postoperative VTE occurred in 6309 patients (0.8%) (DVT in 4336 [0.6%]; PE in 2514 [0.3%]; both DVT and PE in 541 [0.1%]). Perioperative RBC transfusion was associated with higher odds of VTE (aOR, 2.1; 95% CI, 2.0-2.3), DVT (aOR, 2.2; 95% CI, 2.1-2.4), and PE (aOR, 1.9; 95% CI, 1.7-2.1), independent of various putative risk factors. A significant dose-response effect was observed with increased odds of VTE as the number of intraoperative and/or postoperative RBC transfusion events increased (aOR, 2.1 [95% CI, 2.0-2.3] for 1 event; 3.1 [95% CI, 1.7-5.7] for 2 events; and 4.5 [95% CI, 1.0-19.4] for ≥3 events vs no intraoperative or postoperative RBC transfusion; P < .001 for trend). In subgroup analyses, the association between any perioperative RBC transfusion and postoperative VTE remained statistically significant across all surgical subspecialties analyzed. The association between any perioperative RBC transfusion and the development of postoperative VTE also remained robust after 1:1 propensity score matching (47 142 matched pairs; matched OR, 1.9; 95% CI, 1.8-2.1). Conclusions and Relevance: The results of this study suggest that perioperative RBC transfusions may be significantly associated with the development of new or progressive postoperative VTE, independent of several putative confounders. These findings, if validated, should reinforce the importance of rigorous perioperative management of blood transfusion practices.

Approach to pancytopenia: Diagnostic algorithm for clinical hematologists.

Pancytopenia is a relatively common phenomenon encountered in clinical practice. The evaluation of a patient with pancytopenia requires a comprehensive approach and identifying the underlying cause can be challenging given the wide range of etiologies including drugs, autoimmune conditions, malignancies, infections, hemophagocytosis, and inheritable conditions. Recent advances in molecular hematology which include genomic profiling and next-generation sequencing have helped gain major insights into various hematological conditions and can guide diagnosing specific diseases in a shorter time at lower costs. However the approach to manage patients with pancytopenia in the current era of genomics is not well defined in the literature and is widely variable in practice. Herein, we conducted a systematic review to help devise an algorithm and management approach for pancytopenia, which serves as a general consultative approach.

Diagnostic utility of telomere length testing in a hospital-based setting.

Telomere length (TL) predicts the onset of cellular senescence in vitro but the diagnostic utility of TL measurement in clinical settings is not fully known. We tested the value of TL measurement by flow cytometry and FISH (flowFISH) in patients with mutations in telomerase and telomere maintenance genes. TL had a discrete and reproducible normal range with definable upper and lower boundaries. While TL above the 50th age-adjusted percentile had a 100% negative predictive value for clinically relevant mutations, the lower threshold in mutation carriers was age-dependent, and adult mutation carriers often overlapped with the lowest decile of controls. The extent of telomere shortening correlated with the age at diagnosis as well as the short telomere syndrome phenotype. Extremely short TL caused bone marrow failure and immunodeficiency in children and young adults, while milder defects manifested as pulmonary fibrosis-emphysema in adults. We prospectively examined whether TL altered treatment decisions for newly diagnosed idiopathic bone marrow failure patients and found abnormally short TL enriched for patients with mutations in some inherited bone marrow failure genes, such as RUNX1, in addition to telomerase and telomere maintenance genes. The result was actionable, altering the choice of treatment regimen and/or hematopoietic stem cell donor in one-fourth of the cases (9 of 38, 24%). We conclude that TL measurement by flowFISH, when used for targeted clinical indications and in limited settings, can influence treatment decisions in ways that improve outcome.

Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway.

Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations.