The purpose of this review is to provide an updated overview of the pathogenesis and treatment of Langerhans cell histiocytosis (LCH). The pathogenesis of LCH remains obscure and the optimal treatment for LCH has not been established, although incremental progress has been made. Proinflammatory cytokines and chemokines are known to play a role in LCH, which suggests that LCH is an immune disorder. However, the oncogenic BRAF mutation is also detected in more than half of LCH patients, which suggests that LCH is a neoplastic disorder. Remaining major issues in the treatment of LCH are how to rescue patients who have risk-organ involvement but do not respond to first-line therapy, the optimal treatment for the orphan disease of multifocal adult LCH, and how to reduce and treat central nervous system-related consequences, such as central diabetes insipidus and neurodegeneration. More research is needed to better understand the pathogenesis of this disease and to resolve the treatment issues.

The t(4;11)(q21;q23) fuses mixed-lineage leukemia (MLL) to AF4, the most common MLL-fusion partner. Here we show that MLL fused to murine Af4, highly conserved with human AF4, produces high-titer retrovirus permitting efficient transduction of human CD34 cells, thereby generating a model of t(4;11) pro-B acute lymphoblastic leukemia (ALL) that fully recapitulates the immunophenotypic and molecular aspects of the disease. MLL-Af4 induces a B ALL distinct from MLL-AF9 through differential genomic target binding of the fusion proteins leading to specific gene expression patterns. MLL-Af4 cells can assume a myeloid state under environmental pressure but retain lymphoid-lineage potential. Such incongruity was also observed in t(4;11) patients in whom leukemia evaded CD19-directed therapy by undergoing myeloid-lineage switch. Our model provides a valuable tool to unravel the pathogenesis of MLL-AF4 leukemogenesis.

The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4CD8) or CD8 single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

The prognosis of infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcomes was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group trial MLL-10 (registered at umin.ac.jp as UMIN000004801), infants with ALL were stratified into three risk groups (low-risk, LR; intermediate-risk, IR; high-risk, HR) according to KMT2A status, age, and presence of central nervous system leukemia. A modified Children's Oncology Group AALL0631 chemotherapy with addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (N=15), IR (N=19), or HR (N=56). The 3-year event-free survival (EFS) rate (standard error) for patients with KMT2A-r ALL (IR+HR) was 66.2% (5.6%) and 93.3% (6.4%) for those with KMT2A-g ALL (LR). The 3-year EFS rate was 94.4% (5.4%) for IR and 56.6% (6.8%) for HR patients. In multivariable analysis, female sex and MRD ≧0.01% at end of early consolidation were significant poor prognostic factors. Risk stratification and introduction of intensive chemotherapy in the current study were effective and able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials.

Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by XIAP/BIRC4 gene mutations is an inherited immune defect recognized as X-linked lymphoproliferative syndrome type 2. This disease is mainly observed in patients with hemophagocytic lymphohistiocytosis (HLH) often associated with Epstein-Barr virus infection. We described nine Japanese patients from six unrelated families with XIAP deficiency and studied XIAP protein expression, XIAP gene analysis, invariant natural killer T (iNKT) cell counts, and the cytotoxic activity of CD8(+) alloantigen-specific cytotoxic T lymphocytes. Of the nine patients, eight patients presented with symptoms in infancy or early childhood. Five patients presented with recurrent HLH, one of whom had severe HLH and died after cord blood transplantation. One patient presented with colitis, as did another patient's maternal uncle, who died of colitis at 4 years of age prior to diagnosis with XIAP deficiency. Interestingly, a 17-year-old patient was asymptomatic, while his younger brother suffered from recurrent HLH and EBV infection. Seven out of eight patients showed decreased XIAP protein expression. iNKT cells from patients with XIAP deficiency were significantly decreased as compared with age-matched healthy controls. These results in our Japanese cohort are compatible with previous studies, confirming the clinical characteristics of XIAP deficiency.