Chromothriptic cure of WHIM syndrome.

Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.

Menin immunoreactivity in secretory granules of human pancreatic islet cells.

The protein product of the Multiple Endocrine Neoplasia Type I (MEN1) gene is thought to be involved in predominantly nuclear functions; however, immunohistochemical (IHC) analysis data on cellular localization are conflicting. To further investigate menin expression, we analyzed human pancreas (an MEN1 target organ) using IHC analyses and 6 antibodies raised against full-length menin or its peptides. In 10 normal pancreas specimens, 2 independently raised antibodies showed unexpected cytoplasmic immunoreactivity in peripheral cells in each islet examined (over 100 total across all 10 patients). The staining exhibited a distinct punctate pattern and subsequent immunoelectron microscopy indicated the target antigen was in secretory granules. Exocrine pancreas and pancreatic stroma were not immunoreactive. In MEN1 patients, unaffected islets stained similar to those in normal samples but with a more peripheral location of positive cells, whereas hyperplastic islets and tumorlets showed increased and diffuse cytoplasmic staining, respectively. Endocrine tumors from MEN1 patients were negative for menin, consistent with a 2-hit loss of a tumor suppressor gene. Secretory granule localization of menin in a subset of islet cells suggests a function of the protein unique to a target organ of familial endocrine neoplasia, although the IHC data must be interpreted with some caution because of the possibility of antibody cross-reaction. The identity, cellular trafficking, and role of this putative secretory granule-form of menin warrant additional investigation.

Bone marrow findings in HIV-positive patients with Kaposi sarcoma herpesvirus-associated multicentric Castleman disease.

Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus-8, is associated with 1 form of multicentric Castleman disease (MCD) and is the etiologic agent for most MCD in human immunodeficiency virus (HIV)-infected patients. Diagnosis is usually determined by lymph node biopsy. Bone marrow findings in KSHV-MCD are not well characterized. We conducted histomorphologic and immunohistochemical evaluation of bone marrow biopsy specimens in HIV-infected patients with KSHV-MCD, including evaluation for KSHV latency-associated nuclear antigen. Findings were correlated with clinical features and KSHV viral load. Reactive plasmacytosis was the predominant feature. Lymphoid aggregates were less common and not diagnostic of KSHV-MCD. Forty-eight percent of cases contained scattered KSHV-infected mononuclear cells. Although patients were generally cytopenic, bone marrow biopsy specimens were normocellular to hypercellular except in patients receiving hematotoxic therapy. Bone marrow biopsy specimens in KSHV-MCD patients recapitulate findings of interleukin-6 excess. In patients with HIV, unexplained cytopenias, and bone marrow plasmacytosis, evaluation for KSHV-MCD is warranted.

Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival.

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor γ rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.

Adult T-cell leukemia/lymphoma with Epstein-Barr virus-positive Hodgkin-like cells.

Hodgkin-like cells have been described in a variety of non-Hodgkin lymphomas including chronic lymphocytic leukemia and peripheral T-cell lymphoma. There have been rare reports in the Japanese population of human T-cell lymphotrophic virus-1-associated adult T-cell leukemia/lymphoma harboring Hodgkin-like cells; however, no similar cases have been described in Western patients. We report a 53-year-old African American man who presented with progressive weakness and lethargy, and was found to have generalized lymphadenopathy and hypercalcemia. A lymph node biopsy showed involvement by adult T-cell leukemia/lymphoma with scattered Epstein-Barr virus-positive cells, some of which resembled Hodgkin cells that had a B-cell phenotype, consistent with an Epstein-Barr virus-lymphoproliferative disorder. The patient had stage 4 disease with bone marrow involvement. In light of the associated B-cell lymphoproliferative process, the patient was treated with 6 cycles of intensive chemotherapy that targeted both the adult T-cell leukemia/lymphoma and the Epstein-Barr virus-lymphoproliferative disorder that resulted in a complete response. An awareness of the association of Epstein-Barr virus-lymphoproliferative disorder with Hodgkin-like cells in the context of adult T-cell leukemia/lymphoma is necessary to avoid potential misdiagnosis and to aid in therapeutic decisions.