Effective Use of ALK Inhibitors in EML4::ALK-Positive Lymphatic Malformations.

Genetically targeted medications are emerging as important therapies for lymphatic malformations (LMs) unresponsive to sirolimus. We describe two patients with EML4::ALK-positive LMs, one with Gorham Stout disease and one with a large genitourinary (GU) LM, who were successfully treated with ALK inhibitors. This report adds ALK inhibitors to the growing toolbox of molecularly targeted therapies for LMs.

Diagnostic challenges of renal medullary carcinoma and the role for cytologic assessment: Case report and literature review.

Background: Renal medullary carcinoma (RMC) is a diagnostically challenging, aggressive primary renal malignancy associated with abysmal survival. Delays in diagnosis contribute to most patients having diffusely metastatic disease at the time of initial presentation.

Methods: We present the case of a 13-year-old African American male with sickle cell trait who presented with a renal mass and hematuria.

The Heart of the Matter: Secondary Hypogammaglobulinemia and Constrictive Pericarditis.

Constrictive pericarditis is the final common result of a number of processes that affect the pericardium. Establishing the diagnosis and determining the underlying etiology of constrictive pericarditis are often a diagnostic rendezvous. Here, we describe a patient who presented to the general practitioner with edema, ascites, and weight gain and was found to have constrictive pericarditis secondary to an inflammatory myofibroblastic tumor of the mediastinum.

Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis.

The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress.

JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells.

How specific genetic lesions contribute to transformation of non-malignant myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs) to secondary acute myeloid leukemia (sAML) are poorly understood. JARID2 is lost by chromosomal deletions in a proportion of MPN/MDS cases that progress to sAML. In this study, genetic mouse models and patient-derived xenografts demonstrated that JARID2 acts as a tumor suppressor in chronic myeloid disorders.

Granulomatous dermatitis secondary to vemurafenib in a child with Langerhans cell histiocytosis.

We present a 3-year-old boy with Langerhans cell histiocytosis who developed granulomatous dermatitis while taking vemurafenib. Vemurafenib currently has Food and Drug Administration approval for the treatment of BRAF V600E+ metastatic melanoma in adults, but recent discoveries of BRAF V600E in more than half of tested Langerhans cell histiocytosis lesions have prompted clinical trials of vemurafenib therapy for children with refractory, multisystem Langerhans cell histiocytosis. This report contributes to the knowledge of its potential side effects when used in children.

Hematopoietic Cell Transplantation Using Reduced-Intensity Conditioning Is Successful in Children with Hematologic Cytopenias of Genetic Origin.

Genetically derived hematologic cytopenias are a rare heterogeneous group of disorders. Allogeneic hematopoietic cell transplantation (HCT) is curative but offset by organ toxicities from the preparative regimen, graft rejection, graft-versus-host disease (GVHD), or mortality. Because of these possibilities, consideration of HCT can be delayed, especially in the unrelated donor setting.

Enforced differentiation of Dnmt3a-null bone marrow leads to failure with c-Kit mutations driving leukemic transformation.

Genome sequencing studies of patient samples have implicated the involvement of various components of the epigenetic machinery in myeloid diseases, including the de novo DNA methyltransferase DNMT3A. We have recently shown that Dnmt3a is essential for hematopoietic stem cell differentiation. Here, we investigated the effect of loss of Dnmt3a on hematopoietic transformation by forcing the normally quiescent hematopoietic stem cells to divide in vivo.

Clonal-level responses of functionally distinct hematopoietic stem cells to trophic factors.

Recent findings from several groups have identified distinct classes of hematopoietic stem cells (HSCs) in the bone marrow, each with inherent functional biases in terms of their differentiation, self-renewal, proliferation, and lifespan. It has previously been demonstrated that myeloid- and lymphoid-biased HSCs can be prospectively enriched based on their degree of Hoechst dye efflux. In the present study, we used differential Hoechst efflux to enrich lineage-biased HSC subtypes and analyzed their functional potentials.