The Hematopoietic Niche in Myeloproliferative Neoplasms

Specialized microanatomical areas of the bone marrow provide the signals that are mandatory for the maintenance and regulation of hematopoietic stem cells (HSCs) and progenitor cells. A complex microenvironment adjacent to the marrow vasculature (vascular niche) and close to the endosteum (endosteal niche) harbors multiple cell types including mesenchymal stromal cells and their derivatives such as CAR cells expressing high levels of chemokines C-X-C motif ligand 12 and early osteoblastic lineage cells, endothelial cells, and megakaryocytes. The characterization of the cellular and molecular networks operating in the HSC niche has opened new perspectives for the understanding of the bidirectional cross-talk between HSCs and stromal cell populations in normal and malignant conditions. A structural and functional remodeling of the niche may contribute to the development of myeloproliferative neoplasms (MPN). Malignant HSCs may alter the function and survival of MSCs that do not belong to the neoplastic clone. For example, a regression of nestin+ MSCs by apoptosis has been attributed to neuroglial damage in MPN. Nonneoplastic MSCs in turn can promote aggressiveness and drug resistance of malignant cells. In the future, strategies to counteract the pathological interaction between the niche and neoplastic HSCs may offer additional treatment strategies for MPN patients

Case report: Lichenoid esophagitis revealing an HIV infection

Esophageal lichen planus is an underrecognized manifestation of lichen planus. It is typically diagnosed based on characteristic endoscopic findings, such as hyperkeratosis, trachealization, denudation and/or stenosis, along with the presence of a lichenoid infiltrate in histopathological examination. In cases where no other manifestation of lichen planus are found and direct immunofluorescence for fibrinogen along the basement membrane is negative, the term “lichenoid esophagitis” should be preferred. This distinction is critical, as it prompts a thorough evaluation for underlying diseases, including autoimmune conditions and viral infections. We report a case of a 69-year-old male with stenosing esophagitis resembling esophageal lichen planus on endoscopic evaluation. The condition was refractory to multiple dilation procedures and high-dose proton pump inhibitor therapy. Histopathological analysis revealed a dense lymphocytic infiltrate extending into the epithelial layer, while direct immunofluorescence microscopy for fibrinogen was negative. There were no other signs of lichen planus on the skin or mucous membranes. The patient’s medical history included recurrent transient ischemic attack (non-cardiac), penile cancer and recurrent mucosal candidiasis. Laboratory findings revealed Epstein–Barr virus viremia and IgG hypergammaglobulinemia, raising suspicion of immunodeficiency. Further testing confirmed an active HIV infection, classified as category C3, and antiretroviral therapy was initiated. Following the initiation of antiretroviral therapy, the patient experienced rapid clinical and histopathological improvement of the lichenoid esophageal inflammation, although the esophageal stenosis persisted. Subsequent follow-up endoscopies confirmed resolution of the inflammatory component, underscoring the positive impact of addressing the underlying HIV infection on the esophagus. This case report highlights the importance of recognizing lichenoid esophagitis as a potential diagnosis in cases of unexplained chronic esophagitis, especially when standard treatments are ineffective. The presence of lichenoid inflammation without other manifestations of lichen planus should trigger an investigation into underlying conditions

Therapeutic targeting of endoplasmic reticulum stress in acute graft-<i>versus</i>-host disease

Acute graft-versus-host disease (GvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GvHD and can be targeted pharmacologically. We observed high levels of ER stress upon GvHD onset in a murine allo- HCT model and in human biopsies. These levels correlated with GvHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GvHD lethality. This phenotype was mediated by changes in the production of antimicrobial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1α (IRE1α), the most conserved signaling branch in ER stress, reduced GvHD development in mice. IRE1α blockade by the small molecule inhibitor 4m8c improved intestinal cell viability, without impairing hematopoietic regeneration and T-cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GvHD. Reducing ER stress could improve the outcome of patients suffering from GvHD

Prolonged Bone Marrow Failure Following Rituximab Therapy of Follicular Lymphoma

Abstract Prolonged Bone Marrow Failure following Rituximab Therapy of Follicular Lymphoma Laura Debatin, Annette Schmitt-Graeff*, Hendrik Veelken Depts. of Hematology/Oncology and *Pathology, University Medical Center Freiburg Rituximab (R) is a mainstay in B-NHL therapy. Apart from infusional reactions and prolonged B cell depletion, severe R side effects are relatively rare. A 65 year-old, previously healthy woman presented with anemia (Hb 9.3 mg/dl), thrombocytopenia, and cervical lymphadenopathy. A submandibular lymph node biopsy showed CD20+CD10+CD79a+ follicular infiltrates. Diagnosis of follicular lymphoma was supported by detection of an IgH-BCL2 gene rearrangement by FISH. CT scans revealed generalized lymphadenopathy and hepatosplenomegaly. The BM was infiltrated with 68% clonal CD20+CD10+CD79a+ B cells. Due to advanced (stage IVA) and high-risk disease (FLIPI 4/5), 200 mg/m2 cyclophosphamide/100 mg prednisone/day (d) were given for 5 days, followed by a single dose of 375 mg/m2 R. Grade 4 neutropenia developed 4 days later and precluded the planned CHOP chemotherapy. A BM biopsy on d+21 post R showed marked BM hypoplasia consistent with drug-induced changes, but no residual lymphoma. Serologic testing ruled out Parvovirus B19, HBV, HCV and HIV infections. Leukocytes recovered to &amp;gt;1/nl 3,5 weeks after R administration. No further cytoreduction was given due to prolonged cytopenia and documented PR. Despite this history, Bendamustin/R (200 mg) was given for eventual BM relapse at a different hospital 11 months later. Grade 4, filgrastim-refractory cytopenia with the same BM histology developed promptly and lasted for 4 weeks. The patient was transferred to our institution because of multiple opportunistic infections including pulmonary aspergillosis, E. faecium sepsis, and destructive mucor mycosis of the right maxillary sinus. Posaconazole and liposomal amphotericin were given for 5 months. 13 months after the 2nd R infusion, the patient had to undergo reconstructive surgery with a flap plasty to cover an extensive, disfiguring facial and maxillary necrosis. Since different alkylators were given at moderate doses, a causal relationship to similar episodes of rapid-onset, extended BM failure appears unlikely. R, administered immediately prior to both episodes, appears to be the causative agent in this case. Since hematopoietic precursors and the myeloid lineage do not express CD20, the mechanism for this near-fatal BM failure is unknown and suggestive of an idiosyncratic component. The BM findings are incompatible with a metamizol-type allergic agranulocytosis. Severe BM failure appears to be a rare but grave potential side-effect of rituximab.</jats:p