Extramedullary Hematopoiesis Research Articles

Heterotopic Ossification with Intrathyroidal Extramedullary Hematopoiesis in Multifocal Papillary Thyroid Carcinoma: Histopathological Findings and Literature Review.

In recent decades, there has been an increase in the identification of thyroid nodules, both benign and malignant, due to the rise in imaging studies and complementary tests. Among thyroid gland tumors, papillary thyroid carcinoma (PTC) stands out as the most prevalent. Degenerative changes, mainly in the form of nodular goiter, have been recorded, occasionally including areas of calcification and, more rarely, ossification; although the latter seldom progresses to calcinosis. Ectopic bone formation, known as osseous metaplasia, is a rare phenomenon in the thyroid gland, even more so when associated with extramedullary hematopoiesis (EMH), characterized by the presence of hematopoietic elements outside the bone marrow. We present the first documented instance in our country of a patient diagnosed with malignant thyroid nodule, specifically PTC, exhibiting areas of heterotopic ossification with EMH on histopathological examination of the surgical specimen. A possible relationship between heterotopic ossification, EMH, and PTC is suggested. Various growth factors such as bone morphogenetic proteins (BMPs), specific BMP subtypes, and associated receptors could play a crucial role in initiating and developing ectopic bone formation in the context of PTC. However, further research is needed to fully elucidate its clinical significance and impact on the therapeutic management of these patients.

Ultrasonographic characteristics of splenic stromal sarcoma in 13 dogs.

The identification of a solitary splenic mass on abdominal ultrasound is a common occurrence; however, diagnosis based on imaging alone remains a challenge. Multiple studies have tried to identify key characteristics that denote a benign or malignant lesion before splenectomy. Differential diagnoses commonly include hemangiosarcoma, hematoma, extramedullary hematopoiesis, and lymphoid hyperplasia. While comprehensive, this list fails to consider the less frequent neoplasms such as splenic stromal sarcoma. This retrospective study aimed to evaluate 13 dogs diagnosed with canine splenic stromal sarcoma and determine common characteristics noted on abdominal ultrasound. Masses were solid, without evidence of cavitation, and arising from the mid-body of the spleen. While abdominal ultrasound does not provide a definitive diagnosis for splenic stromal sarcoma, it should be considered when identifying a solitary, solid, noncavitary splenic mass.

Perinephric Myxoid Pseudotumor of Fat: A Series of 13 Cases and Literature Review

Perinephric myxoid pseudotumor of fat (PMPF) is a recently described and rare retroperitoneal mass-forming lesion whose clinical significance chiefly involves mimicry of a variety of soft tissue tumors. For unknown reasons, it commonly occurs in male patients with underlying non-neoplastic renal diseases and/or type 2 diabetes (DMT2). A total of 55 cases have been reported in the literature. Recently, we have encountered 13 such masses with peculiar histologic features; thus, we sought to investigate our experience and review the clinicopathologic characteristics of the literature. Our series confirms that PMPF frequently occurs in adult male patients (11/13, 85%), with an average age of 66 years, and commonly co-occurs with renal disease, such as DMT2 (2/13, 15%), end-stage renal disease (ESRD) (5/13, 39%), renal cysts (4/13, 31%), concurrent or prior renal neoplasia (2/13; 15%), and myeloma/lymphoma (2/13; 15%). Histologic evaluation shows lipomatous masses commonly showing variable amounts of fat necrosis, myxoid degeneration, lymphoplasmacytic inflammation and lacking atypical hyperchromatic stromal spindle cells. Unusual histologic features include extramedullary hematopoiesis (1/13, 8%), hemosiderin deposition (4/13, 31%), and small wisps of mature smooth muscle (6/13, 46%). All cases tested were negative for MDM2 and did not show an increased ratio of IgG4+/IgG+ plasma cells. Our study confirms the clinical and pathologic features of PMPF and expands its histologic spectrum, underscoring the importance of this entity as a benign pseudotumor which should be included in the differential diagnosis of other fat-containing retroperitoneal masses, particularly well-differentiated liposarcoma.

Historical Control Background Incidence of Spontaneous Nonneoplastic Lesions of Sprague Dawley Rats in 104-Week Carcinogenicity Studies.

Microscopic observation data collected from approximately 1800 male and female Sprague Dawley (SD) control rats used on 104-week carcinogenicity studies performed at North American Labcorp Early Development, Inc, Madison, WI, were retrospectively evaluated for spontaneous nonneoplastic findings. This study provides incidence of the most common spontaneous nonneoplastic microscopic findings in each organ system of SD rats encountered during 104-week carcinogenicity studies. Some of the most common spontaneous background findings were cardiomyopathy; chronic progressive nephropathy; uterine cystic endometrial hyperplasia; prostate inflammation; pulmonary alveolar macrophage infiltrates; hepatocyte vacuolation, bile duct hyperplasia, and basophilic foci in the liver; pancreatic fibrosis; splenic extramedullary hematopoiesis and pigment; decreased lymphocytes and epithelial hyperplasia in the thymus; ventral brain compression; cystic degeneration and hyperplasia of the adrenal cortex; and mammary gland hyperplasia. The most common nonneoplastic findings in male SD rats were chronic progressive nephropathy (80.9%) and rodent progressive cardiomyopathy (73.2%). The most common nonnenoplastic findings in female SD rats were cystic degeneration of the adrenal cortex (64.7%) and ventral compression of the brain due to pituitary neoplasms (62.7%).

A case report of mediastinal extramedullary hematopoiesis: imaging, pathological and thoracoscopic biopsy correlation

ObjectiveTo summarize the clinical features, imaging characteristics, and surgical diagnosis and treatment experience of mediastinal extramedullary hematopoiesis.MethodsBy summarizing and analyzing the case data and reviewing the literature, one case of posterior mediastinal extramedullary hematopoiesis on thoracoscopic biopsy in our department was summarized.ConclusionPosterior mediastinal extramedullary hematopoiesis is a response to failure of bone marrow erythropoiesis, which is relatively rare clinically, and diagnosis requires a combination of patient history and imaging, puncture biopsy or thoracoscopic excisional biopsy can provide a pathological diagnosis, and surgical complete resection is the main treatment modality.

Case Series: Unveiling mass-forming neoplastic extramedullary hematopoiesis in chronic myeloid leukemia

Abstract Introduction/Objective Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by BCR::ABL1 fusion and predominantly granulocytic proliferation. Three main phases of disease have previously been recognized: chronic, accelerated and blast phase, though accelerated phase has become controversial. During the chronic phase, leukemic cells exist predominantly in the peripheral blood and bone marrow; however, during blast phase, blasts can proliferate in the blood, bone marrow, or extramedullary tissues. Methods/Case Report We present two instances of cutaneous extramedullary hematopoiesis associated with CML at our institution. Results (if a Case Study enter NA) Case 1: A 34-year-old man previously diagnosed with CML presented with painful pustules on his right thigh. Biopsy revealed an infiltration of primarily left-shifted granulocytes, along with scattered megakaryocytes, and rare erythroid precursors. Immunohistochemical studies were consistent with maturing extramedullary hematopoiesis, devoid of sheets or clusters of blasts. Peripheral blood analysis revealed marked neutrophilic leukocytosis with basophilia and eosinophilia. Bone marrow examination depicted left-shifted granulocytic hyperplasia, megakaryocytic hyperplasia, and fewer than 5% blasts. Case 2: A 40-year-old man presented with fatigue, night sweats, weight loss, hepatosplenomegaly and palpable nodules on his left arm and thighs. The biopsy of the thigh nodule uncovered leukemic cells at different developmental stages, along with eosinophils, erythroid precursors, and megakaryocytes. Immunohistochemical staining confirmed their presence, with only a few blasts observed. Blood and bone marrow tests showed leukocytosis with blasts less than 5%, indicating CML in the chronic phase. Molecular analysis confirmed BCR-ABL1 fusion. Conclusion Mass-forming neoplastic extramedullary hematopoiesis in the skin during chronic phase of CML is a feature that is not well-documented in the literature. This entity shows immature granulocytic precursors, but does not exhibit an increase in blasts and therefore should not be called leukemia cutis or myeloid sarcoma. It is important to raise awareness of this entity to prevent misinterpretation as myeloid sarcoma and subsequent unnecessarily aggressive therapy.

Sclerosing Extramedullary Hematopoietic Tumor of the Breast

Abstract Introduction/Objective Sclerosing extramedullary hematopoietic tumor (SEMHT) is a rare tumor that occurs in patients with chronic myeloproliferative conditions. SEMHT can be seen in abdominal organs, retroperitoneum and mesentery. It can also be regarded as an advanced manifestation of myelofibrosis. SEMHT can occur singly or as multiple masses and manifests later in the disease course of CMPD. The differential diagnosis includes breast cancer, soft tissue tumor, and extramedullary hematopoiesis. Here we present a case of SEMHT in the breast. Methods/Case Report This is a 80-year-old female, who has a history of left breast ductal carcinoma in situ who underwent lumpectomy and received radiation in 2020. The patient also has Polycythemia Vera and MF. Bone marrow aspiration, Trephine biopsy imprints and Trephine and clot biopsies showed persistent myelofibrotic myeloid neoplasm involving a cellular bone marrow with marked fibrosis (MF Grade 3), megakaryoblastic hyperplasia, atypical megakaryocytes. In 3/2023, there were two small masses found in upper outer right breast by ultrasound measuring 4 mm and 3 mm in diameter. Breast biopsy sections showed scattered rare atypical cells within fibrotic stroma. They were only positive for Vimentin and Androgen Receptor (rare) within the performed immunohostochemistry panel. Ki67 proliferation index was 20%. The biopsy report was signed out as aytpical mesenchymal tumor. Resection was recommended. The resection showed same atypical cells within large sclerotic stroma. These atypical cells were scattered in the breast tissue along with sinusoidal capillarization. The atypical cells were atypical megakaryocytes highlighted with CD61. Erythrocyte precursors are highlighted with glycophorin a. Based on the clinical history and histologic features, SEMHT diagnosis was made. Results (if a Case Study enter NA) NA due to being a case study. Conclusion SEMHT is a rare tumor, that can occur in patients with CMPD. It can occur within different locations in the body, including breast. SEHMT should be kept in mind for an accurate diagnosis of the tumor and correct management of the patients.

Plasma sphingomyelin levels were negatively correlated with ferritin levels in splenectomized thalassemia patients

Abstract Beta thalassemia results from decreased production of beta chains due to either mutations or deletions in the beta-globin gene, leading to impaired production of hemoglobin A. Thalassemia patients take frequent blood transfusions to compensate for hemolytic anemia and iron overload. Iron overload is monitored by serum ferritin levels in these patients. Extra-medullary hematopoiesis in beta thalassemia major leads to hypersplenism which often necessitates splenectomy to increase red cell life span and decrease transfusion need. Sphingomyelin is the second most abundant phospholipid in human plasma after phosphatidylcholine. In contrast to the well-defined roles of sphingolipids in cell membranes, their possible physiological role in lipoprotein metabolism has recently gained attention. Increased circulating levels of sphingomyelins and ceramides were observed in obesity, diabetes, and cardiovascular diseases. Although lipid abnormalities such as hypocholesterolemia and relatively increased triglycerides were reported in beta-thalassemia patients, there is no study investigating sphingolipid levels in thalassemia. Therefore, we investigate certain long chain and very long chain sphingomyelins and ceramides in beta-thalassemia patients who are under routine follow-up in our hospital. Thalassemia major patients who applied to the hospital for regular blood transfusion and gave consent were included in the study. Blood samples were obtained before transfusion. Plasma sphingomyelin (C16, C18 and C24) and ceramide (C16, C18, C20, C22, C24) species were measured by triple quadruple LC-ESI-MS/MS (Shimadzu, Japan). D-erythrosphingosine-D9 (Matreya) was used as an internal standard, all other lipid standards were from Avanti. Body iron stores of the patients were monitored by serum ferritin levels. A total of thirty patients were included in the study. All patients typically received regular erythrocyte suspension transfusions every three weeks and continuous oral iron chelation therapy. Twenty of the patients had a previous splenectomy. The mean age was 34.5 ±8.1 years in the splenectomy group and 32.8 ±8 years in the group without splenectomy. Mean ferritin levels were not different between the groups, being 1073.2±563.5 µg/L in splenectomy and 1709 ±1660.4 µg/L in non-splenectomy groups. All measured sphingolipid levels were similar between splenectomy and non-splenectomy groups. When correlation analysis was performed between measured sphingolipid and ferritin levels, significant negative correlations were found between sphingomyelin C16 (r= -0.591 p<0.006) and C18 (r= -0.594 p<0.006) with ferritin levels in the splenectomy group. However, this negative correlation was absent in the non-splenectomy group. In conclusion, we found that iron overload is associated with lower plasma sphingomyelin levels in splenectomized thalassemia patients. We have been working on the lipidomic analysis of the plasma and erythrocytes of thalassemia patients and other hemolytic anemias. The results may further help to get a better picture of lipid metabolism in thalassemia.

DICER1 Mutations Enable Rare Tumor Formation

Abstract Introduction/Objective DICER1 is a tumor suppressor gene that imparts a slight increase in tumor formation when mutated. The protein plays a role in processing miRNA that silences transcription. Germline mutations of DICER1 predispose to tumors in a known set of organs and rarely in other locations. However the presence of additional genetic aberrations further increases the likelihood of tumor formation. Acting as a compounding factor, DICER1 mutations can present a constantly shifting cancer phenotype of affected patients. Of particular interest here is the development of both Pineoblastoma and Malignant spindle cell sarcoma in a young patient. Sarcomas are estimated to make up only 10% of pediatric cancers and Pineal masses only 3%. Methods/Case Report This case involves an 8 year old male with a history of Pineoblastoma who originally presented with slowly worsening ataxia. A screening ultrasound on following visits identified an abdominal mass that was confirmed with computed tomography. Subsequent biopsies showed malignant spindle cells arranged in a herringbone pattern. Additionally these cells displayed high mitotic activity and hyperchromatic nuclei. Surprisingly, they also demonstrated extramedullary hematopoiesis. Multiple stains were performed however no significant conclusion could be made. The appearance of this tumor and its rarity prompted a request for a Complete Comprehensive Sarcoma Panel via Next Generation Sequencing. This confirmed the presence of pathologic BRAF and DICER1 genes. From that the diagnosis of DICER1 associated Malignant Spindle Cell Sarcoma was made. BRAF V600E is the most common genetic variant and is seen in multiple cancers but only seen in 1-3% of sarcomas. Pathologic variants of the DICER1 gene exist on exons 13 and 25. The presence of these exon mutations in some way affect DICER1 protein function and compound the effects of the mutated BRAF gene. This situation is unique as such neoplasms are rarely found in the anterior abdominal wall and showcases the effects of DICER1 on rare tumor phenotypes. Results (if a Case Study enter NA) NA Conclusion Continuing research into both DICER1 protein pathways is essential for isolating a diagnosis and guiding treatment. It would seem screening images and genetic testing would benefit pediatric or even adult patients with common and rare cancers. Extra effort made toward this would not be outside the norm as personalized medicine is gradually becoming the standard for cancer treatment.

Angiomyolipomatous Lesions of the Nasal Cavity (Sinonasal Angioleiomyoma with Adipocytic Differentiation): A Multi-Institutional Immunohistochemical and Molecular Study.

Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. Fifteen lesions (3-42mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88-12.4). Morphologically, 11 AML contained 30-80% smooth muscle, 10-25% vasculature, and 2-60% adipose tissue, while four AL contained 70-80% smooth muscle and 20-30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components.

8194 Extramedullary Hematopoiesis Involving Bilateral Adrenal Glands In A Patient With Sickle Cell Anemia

Abstract Disclosure: V.T. Pham: None. L.N. Sendos: None. Title: Extramedullary hematopoiesis involving bilateral adrenal glands in a patient with sickle cell anemia Background: Extramedullary hematopoiesis refers to blood cell production occurring outside the bone marrow. It is a reactive process caused by inadequate production or excessive destruction of blood cells typically seen in patients with hereditary anemias or infiltrative bone marrow disorders. Extramedullary hematopoiesis usually occurs in the spleen, liver and lymph nodes, but it can also very rarely arise from the adrenal glands. Case Presentation:We present a case of a 42-year-old male with a history of sickle cell anemia who presented with chest pain and shortness of breath and had a chest CT angiography which incidentally showed a 5.6 x 3.8 cm left adrenal mass and a 2.9 x 2.1 cm right adrenal mass. Further evaluation with an MRI abdomen with and without contrast revealed a 5.5 cm lobulated left adrenal mass with patchy areas of microscopic fat and faint delayed heterogeneous enhancement as well as a 2.2 cm right adrenal nodule. The nodules were described as markedly T2 hypointense with heterogeneous T1 hyperintense/isointense signal on MRI with a broad differential diagnosis including extramedullary hematopoiesis in bilateral adrenal glands, lipid poor adenoma or neoplasm. Regarding his sickle cell disease history, the patient was diagnosed as an infant and had very rare episodes of sickle cell pain crisis as a child. However, once he entered adulthood, he began to have multiple episodes of sickle cell pain crisis requiring hospitalizations and transfusions. On further review of patient’s prior imaging scans during these previous hospitalizations, he was first noted to have bilateral sub centimeter adrenal nodules on a CT Abdomen without contrast done almost a decade prior to his current presentation. We ordered biochemical evaluation which did not show any evidence of adrenal hormonal hypersecretion. His case was discussed at our multidisciplinary conference with the radiology and surgery team and it was concluded that the imaging characteristics were most consistent with extramedullary hematopoiesis in the setting of bilateral adrenal gland involvement and patient’s history of sickle cell anemia. Therefore, no immediate surgical resection was recommended. Given the size of the left adrenal mass being greater than 4 cm in size, we advised follow-up imaging for surveillance. Discussion:There has been a rise in detection of adrenal incidentalomas due to the increased use of advanced diagnostic imaging in healthcare settings. When patients with hematologic diseases are found to have adrenal incidentalomas, it is important to consider extramedullary hematopoiesis in the differential diagnosis to avoid unnecessary invasive procedures and surgeries. Presentation: 6/2/2024

Myeloid deficiency of heparan sulfate 6-O-endosulfatases impairs bone marrow hematopoiesis

The heparan sulfate (HS) 6-O-endosulfatases or the Sulfs (Sulf1 and Sulf2) are the only known enzymes that can modify HS sulfation status extracellularly and have been shown to regulate diverse biological processes. The role of the Sulfs in bone marrow (BM) hematopoiesis is not known. In this study, we generated a novel mouse line with myeloid-specific deletion of the Sulfs by crossing Sulf1/2 double floxed mice with the LysM-cre line. The LysM-Sulf knockout (KO) male mice exhibited age-dependent expansion of hematopoietic stem cells and the granulocyte-monocyte lineages in the BM, whereas common lymphoid progenitors and B lymphocyte populations were significantly reduced. Although megakaryocytic and erythroid progenitors were not reduced in the BM, the LysM-Sulf KO males suffered age-dependent reduction of red blood cells (RBCs) and platelets in the peripheral blood, suggesting that the production of RBCs and platelets was arrested at later stages. In addition, LysM-Sulf KO males displayed progressive splenomegaly with extramedullary hematopoiesis. Compared to males, LysM-Sulf KO females exhibited a much-reduced phenotype, and ovariectomy had little effect. Mechanistically, reduced TGF-β/Smad2 but enhanced p53/p21 signaling were observed in male but not female LysM-Sulf KO mice. Finally, HS disaccharide analysis via LC-MS/MS revealed increased HS 6-O-sulfation in the BM from both male and female LysM-Sulf KO mice, however, the distribution of 6-O-sulfated motifs were different between the sexes with compensatory increase in Sulf1 expression observed only in LysM-Sulf KO females. In conclusion, our study reveals that myeloid deficiency of the Sulfs leads to multilineage abnormalities in BM hematopoiesis in an age- and sex-dependent manner.

Disruption of the PGE2 synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice.

Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs still limits their clinical utility. Combinatorial strategies enhance the antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs. Prostaglandin (PG) E2, formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE2 synthesis /response pathway- global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4- on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr KO) mice. All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE2 biosynthesis, reflected by its major urinary metabolite, PGE2 biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4 KO mice as impaired. in Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.

Correction of osteopetrosis in the neonate oc/oc murine model after lentiviral vector gene therapy and non-genotoxic conditioning.

Autosomal recessive osteopetrosis (ARO) is a rare genetic disease, characterized by increased bone density due to defective osteoclast function. Most of the cases are due to TCIRG1 gene mutation, leading to severe bone phenotype and death in the first years of life. The standard therapy is the hematopoietic stem cell transplantation (HSCT), but its success is limited by several constraints. Conversely, gene therapy (GT) could minimize the immune-mediated complications of allogeneic HSCT and offer a prompt treatment to these patients. The Tcirg1-defective oc/oc mouse model displays a short lifespan and high bone density, closely mirroring the human condition. In this work, we exploited the oc/oc neonate mice to optimize the critical steps for a successful therapy. First, we showed that lentiviral vector GT can revert the osteopetrotic bone phenotype, allowing long-term survival and reducing extramedullary haematopoiesis. Then, we demonstrated that plerixafor-induced mobilization can further increase the high number of HSPCs circulating in peripheral blood, facilitating the collection of adequate numbers of cells for therapeutic purposes. Finally, pre-transplant non-genotoxic conditioning allowed the stable engraftment of HSPCs, albeit at lower level than conventional total body irradiation, and led to long-term survival and correction of bone phenotype, in the absence of acute toxicity. These results will pave the way to the implementation of an effective GT protocol, reducing the transplant-related complication risks in the very young and severely affected ARO patients.

Clonal monocytosis of renal significance

Clonal monocytosis reflects a preneoplastic or neoplastic sustained increase in the absolute monocyte count in the absence of reactive causes. Causes of clonal monocytosis include clonal cytopenias with monocytosis and acute and chronic myeloid neoplasms. Chronic myelomonocytic leukemia is a prototypical myelodysplastic/myeloproliferative overlap neoplasm in adults, characterized by sustained peripheral blood monocytosis. Renal abnormalities, including acute kidney injury and chronic kidney disease, are frequent in patients with chronic myelomonocytic leukemia and are predictors of worse outcomes. In addition, acute kidney injury/chronic kidney disease often limits eligibility for allogeneic stem cell transplantation or enrollment in clinical trials. In this review, we highlight clonal monocytosis-related etiologies that give rise to acute kidney injury and chronic kidney disease, with special emphasis on chronic myelomonocytic leukemia and lysozyme-induced nephropathy. Monocytes produce lysozyme, which, in excess, can accumulate in and damage the proximal renal tubular epithelium. Early identification of this etiology and a timely reduction in monocyte counts can salvage renal function. Other etiologies of renal injury associated with clonal monocytosis include direct renal infiltration by monocytes, renal extramedullary hematopoiesis, myeloproliferative neoplasm-associated glomerulopathy, autoimmune (membranous nephropathy, minimal change disease) and paraneoplastic manifestations, thrombotic microangiopathy, obstructive nephropathy due to myeloproliferation, and urate nephropathy due to tumor lysis syndrome. We propose to group these mechanistic etiologies of renal injury as clonal monocytosis of renal significance and provide guidance on their diagnosis and management.

Splenectomy unveils thrombocytosis in underlying myeloproliferative neoplasms with extrahepatic portal vein obstruction.

Extrahepatic portal vein obstruction (EHPVO) is a rare disease with myeloproliferative neoplasm (MPN) as the most common cause. We report that hypersplenic hematologic changes in EHPVO might be eliminated by MPN. Through experience with splenectomy for variceal control with EHPVO, we suspected that spleen might mask MPN-induced thrombocytosis, and that MPN might have a significant influence on excessive thrombocytosis after splenectomy. To clarify the influence of MPN and spleen on platelet trends, we conducted a retrospective hospital database analysis, evaluating 8 EHPVO patients with splenectomy (2 males, 6 females; from 17 years to 64 years, mean 38.3 years). Three (37.5%) of 8 were diagnosed as MPN by JAK2V617F mutation. The perioperative serum platelet counts in EHPVO without MPN were 10.5, 35.4, and 36.6 (x104/μL) preoperatively, after 1 week and 3 weeks, respectively. The platelet counts in EHPVO with MPN were 34.2, 86.4, and 137.0 (x104/μL), respectively. Splenectomy and MPN showed positive interaction on platelet increasing with statistical significance. We also examined the spleen volume index (SpVI: splenic volume (cm3) / body surface area (m2) and postoperative platelet elevations ratio (PER: 3-week postoperative platelet counts / preoperative platelet counts). However, both SpVI and PER showed no significant difference with or without MPN. Histological examination revealed splenic congestion in all 8 EHPVO cases, and splenic extramedullary hematopoiesis in 2 of 3 MPN. In EHPVO with MPN, hypersplenism causes feigned normalization of platelet count by masking MPN-induced thrombocytosis; however, splenectomy unveils postoperative thrombocytosis. Spleen in EHPVO with MPN also participates in extramedullary hematopoiesis.

Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis.

Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans. The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation. All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis. This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.

Rare glomerulopathy associated with renal extramedullary hematopoiesis in a patient with primary myelofibrosis: A case report

Rare glomerulopathy associated with renal extramedullary hematopoiesis in a patient with primary myelofibrosis: A case report

The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression.

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.

Endothelial LATS2 is a suppressor of bone marrow fibrosis

Myelofibrosis and osteosclerosis are fibrotic diseases disrupting bone marrow function that occur in various leukemias but also in response to non-malignant alterations in hematopoietic cells. Here we show that endothelial cell–specific inactivation of the Lats2 gene, encoding Hippo kinase large tumor suppressor kinase 2, or overexpression of the downstream effector YAP1 induce myofibroblast formation and lead to extensive fibrosis and osteosclerosis, which impair bone marrow function and cause extramedullary hematopoiesis in the spleen. Mechanistically, loss of LATS2 induces endothelial-to-mesenchymal transition, resulting in increased expression of extracellular matrix and secreted signaling molecules. Changes in endothelial cells involve increased expression of serum response factor target genes, and, strikingly, major aspects of the LATS2 mutant phenotype are rescued by inactivation of the Srf gene. These findings identify the endothelium as a driver of bone marrow fibrosis, which improves understanding of myelofibrotic and osteosclerotic diseases, for which drug therapies are currently lacking.