Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia.

The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program.

Multidisciplinary management of disseminated Exophiala dermatitidis mycosis in an infant with mixed phenotype acute leukemia: a case report.

Background: Exophiala dermatitidis is a dematiaceous fungus isolated from various environmental sources. Systemic E. dermatitidis infections can lead to fatal outcomes, and treatment has not yet been standardized.

ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.

Unlabelled: ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but their mechanistic role in leukemogenesis and lineage ambiguity is poorly understood. Using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPC) and a Ep300::Znf384 knockin mouse model, we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged xenograft to FLT3 inhibition in vivo.

Clonal evidence for the development of neuroblastoma with extensive copy-neutral loss of heterozygosity arising in a mature teratoma.

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma.

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia.

The genetic basis and cell of origin of mixed phenotype acute leukaemia.

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia.

Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia.

Somatic genetic alterations of IKZF1, which encodes the lymphoid transcription factor IKAROS, are common in high-risk B-progenitor acute lymphoblastic leukemia (ALL) and are associated with poor prognosis. Such alterations result in the acquisition of stem cell-like features, overexpression of adhesion molecules causing aberrant cell-cell and cell-stroma interaction, and decreased sensitivity to tyrosine kinase inhibitors. Here we report coding germline IKZF1 variation in familial childhood ALL and 0.

Phase I study of glypican-3-derived peptide vaccine therapy for patients with refractory pediatric solid tumors.

The carcinoembryonic antigen glypican-3 (GPC3) is a good target of anticancer immunotherapy against pediatric solid tumors expressing GPC3. In this non-randomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3-peptide vaccination in patients with pediatric solid tumors. Eighteen patients with pediatric solid tumors expressing GPC3 underwent GPC3-peptide vaccination (intradermal injections every 2 weeks), with the primary endpoint being the safety of GPC3-peptide vaccination and the secondary endpoints being immune response, as measured by interferon (IFN)-γ enzyme-linked immunospot assay and Dextramer staining, and the clinical outcomes of tumor response, progression free survival (PFS), and overall survival (OS).

Infantile fibrosarcoma treated with postoperative vincristine and dactinomycin.

Infantile fibrosarcoma is a non-rhabdomyosarcoma soft-tissue sarcoma that occurs in infancy and which has a relatively good prognosis. A vincristine and dactinomycin (VA) regimen has been shown to be effective, although the duration of chemotherapy has not been well defined. We describe the case of a 4-month-old boy with a mass at the left dorsum of the foot who was diagnosed with infantile fibrosarcoma after resection of the tumor, the margin of which was macroscopically positive.

Haploidentical hematopoietic cell transplantation for disseminated Ewing sarcoma.

We describe the case of a 13-year-old girl with multifocal disseminated Ewing sarcoma family of tumor (ESFT) who received a 5/8 human leukocyte antigen-matched haploidentical hematopoietic cell transplantation to generate a graft-versus-tumor effect. The patient had grade 2 acute graft-versus-host disease (GVHD) of the skin and chronic GVHD nausea and abdominal pain that required prednisolone for 17 months, but has been free from ESFT for 3 years 10 months after therapy. The present case suggests a beneficial effect of haploidentical hematopoietic cell transplantation in disseminated ESFT.

Risk Factors for Hospital-acquired Clostridium difficile Infection Among Pediatric Patients With Cancer.

Hospital-acquired Clostridium difficile infection (CDI) may cause life-threatening colitis for children with cancer, making identification of risk factors important. We described characteristics of pediatric cancer patients with primary and recurring CDI, and evaluated potential risk factors. Among 189 cancer patients, 51 cases (27%) of CDI and 94 matched controls of cancer patients without CDI were analyzed.

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia.

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL). Here we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG is a hallmark of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion.

[Severe 6-mercaptopurine-induced hematotoxicity in childhood an ALL patient with homozygous NUDT15 missence variants].

Thiopurine S-methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants are considered to be genes responsible for severe myelotoxicity induced by 6-mercaptopurine (6MP). We report a 4-year-old girl with acute lymphoblastic leukemia, who developed the complication of severe 6MP-induced myelotoxicity due to homozygous NUDT15 variant alleles. In early consolidation therapy containing 6MP, her course was complicated by severe neutropenia (Grade 4) and chemotherapy had to be discontinued for 33 days.

Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide.

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14-year-old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy.

Phosphoproteome analysis of formalin-fixed and paraffin-embedded tissue sections mounted on microscope slides.

Formalin-fixed and paraffin-embedded (FFPE) sections mounted on microscope slides are one of the largest available resources for retrospective research on various diseases, but quantitative phosphoproteome analysis of FFPE sections has never been achieved because of the extreme difficulty of procuring sufficient phosphopeptides from the limited amounts of proteins on the slides. Here, we present the first protocol for quantitative phosphoproteome analysis of FFPE sections by utilizing phase-transfer surfactant-aided extraction/tryptic digestion of FFPE proteins followed by high-recovery phosphopeptide enrichment via lactic acid-modified titania chromatography. We established that FFPE sections retain a similar phosphoproteome to fresh tissue specimens during storage for at least 9 months, confirming the utility of our method for evaluating phosphorylation profiles in various diseases.

Trunk exoskeleton in teleosts is mesodermal in origin.

The vertebrate mineralized skeleton is known to have first emerged as an exoskeleton that extensively covered the fossil jawless fish. The evolutionary origin of this exoskeleton has long been attributed to the emergence of the neural crest, but experimental evaluation for this is still poor. Here we determine the embryonic origin of scales and fin rays of medaka (teleost trunk exoskeletons) by applying long-term cell labelling methods, and demonstrate that both tissues are mesodermal in origin.

p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70.

Cell cycle regulators play critical roles in the balance between hematopoietic stem cell (HSC) dormancy and proliferation. In this study, we report that cell cycle entry proceeded normally in HSCs null for cyclin-dependent kinase (CDK) inhibitor p57 due to compensatory upregulation of p27. HSCs null for both p57 and p27, however, were more proliferative and had reduced capacity to engraft in transplantation.

Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells.

The endosteal niche is critical for the maintenance of hematopoietic stem cells (HSCs). However, it consists of a heterogeneous population in terms of differentiation stage and function. In this study, we characterized endosteal cell populations and examined their ability to maintain HSCs.

Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells.

During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA.

Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells.

Objective: Angiopoietin-1 (Ang-1) plays a critical role in the maintenance of hematopoietic stem cells (HSCs) in the bone marrow (BM) through its binding to the Tie2 receptor. Ang-2, another Tie2 ligand, is known to be an antagonist of Tie2/Ang-1 signaling in angiogenesis; however, its function in regulation of HSCs remains unclear. Here, we investigated the functional differences between Ang-1 and Ang-2 in the maintenance of HSCs.

Niche regulation of hematopoietic stem cells in the endosteum.

During postnatal life, the bone marrow (BM) supports both the self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches. The interaction of HSCs with their niches also regulates the quiescence of HSCs. HSC quiescence is critical to ensure lifelong hematopoiesis and to protect the HSC pool from myelotoxic insult and premature exhaustion under conditions of hematopoietic stress.