Olive S. Eckstein

Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes

Mixed-phenotype acute leukemia (MPAL) is a heterogeneous group of poor-prognosis leukemias with immunophenotypic features of at least two cell lineages. The full spectrum of genetic mutations in this rare disease has not been elucidated, limiting our understanding of disease pathogenesis and our ability to devise targeted therapeutic strategies. Here, we sought to define the mutational landscape of MPAL by performing whole-exome sequencing on samples from 23 adult and pediatric MPAL patients. We identified frequent mutations of epigenetic modifiers, most notably mutations of DNMT3A, in 33% of adult MPAL patients. Mutations of activated signaling pathways, tumor suppressors, and transcription factors were also frequent. Importantly, many of the identified mutations are potentially therapeutically targetable, with agents currently available or in various stages of clinical development. Therefore, the mutational spectrum that we have identified provides potential biological insights and is likely to have clinical relevance for patients with this poor-prognosis disease.

Activating MAPK1 (ERK2) mutation in an aggressive case of disseminated juvenile xanthogranuloma

Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder that is usually benign and self-limiting. We present a case of atypical, aggressive JXG harboring a novel mitogen-activated protein kinase (MAPK) pathway mutation in the MAPK1 gene, which encodes mitogen-activated protein kinase 1 or extracellular signal-regulated 2 (ERK2). Our analysis revealed that the mutation results in constitutive ERK activation that is resistant to BRAF or MEK inhibitors but susceptible to an ERK inhibitor. These data highlight the importance of identifying specific MAPK pathway alterations as part of the diagnostic workup for patients with histiocytic disorders rather than initiating empiric treatment with MEK inhibitors.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

A genome-wide association study of LCH identifies a variant in SMAD6 associated with susceptibility

To the editor: Langerhans cell histiocytosis (LCH) is a hematologic disorder that presents with a wide spectrum of symptoms, ranging from focal lesions to potentially lethal multiorgan disease, affecting 4 to 8 per million children per year[1][1] and 1 to 2 per million adults per year.[2][2]

Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations

Treatment of the autoimmune and immune-dysregulatory features of patients with STAT1 GOF or STAT3 GOF disease remains challenging. Jakinibs have been used to treat the severe immune-dysregulation in patients with either STAT1 GOF or STAT3 GOF mutations.

Evaluation of maternal and perinatal characteristics on childhood lymphoma risk: A population-based case-control study.

Lymphoma is one of the most common pediatric malignancies; however, there are few well‐established risk factors. Therefore, we investigated if maternal and perinatal characteristics influenced the risk of childhood lymphoma.

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

Central nervous system Langerhans cell histiocytosis (CNS‐LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH‐ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS‐LCH.