Transient Myeloproliferative Disorder as the Presenting Feature for Mosaic Trisomy 21

Trisomy 21 is a common congenital disorder with well documented clinical manifestations, including an increased risk for transient myeloproliferative disorder as a neonate and leukemia in childhood and adolescence. Children with mosaic trisomy 21 can have a similar risk for hematological malignancies. We present a non-dysmorphic neonate, with negative noninvasive prenatal screening of maternal blood for trisomy 21, who came to medical attention because of ruddy skin. He was found to have mild polycythemia, thrombocytopenia and developed peripheral blasts. His clinical presentation was concerning for transient myeloproliferative disorder, which is only seen in trisomy 21 patients. Cytogenetic studies were positive for mosaic trisomy 21.

Disseminated tuberculosis with myelofibrosis presentation: a case report

Background Primary myelofibrosis is a rare myeloproliferative disorder in middle-aged and old adults and should be distinguished from secondary and reactive causes of bone marrow fibrosis because, in reactive fibrosis, treatment approaches depend on the underlying etiology. Case presentation Here we report the case of a middle-aged Iranian man who was diagnosed and treated as primary myelofibrosis at presentation, and whose final diagnosis was disseminated tuberculosis with reactive bone marrow fibrosis. Conclusions It is prudent to evaluate the potential causes of myelofibrosis in any patient with the diagnosis primary myelofibrosis. Tuberculosis can be an important etiology of bone marrow fibrosis, especially in endemic areas.

Hydrogel-Based 3D Culture Model for Down Syndrome Associated Transient Myeloproliferative Disorder Using Customized Induced Pluripotent Stem Cells

The generation of hematopoietic stem and progenitor cells (HSPCs) from induced pluripotent stem cells (iPSCs) provides an extraordinary tool for hematological disease modeling of rare disorders such as Down syndrome (DS) associated transient myeloproliferative disorder (TMD). TMD is a preleukemic condition observed in 10-20% of children with trisomy 21 possessing the pathognomonic mutation in the transcription factor GATA1. Hematopoiesis in the bone marrow (BM) is affected by cell-cell and cell-matrix interactions. The current methods for iPSC differentiation into HSPCs utilize either 2-dimensional (2D) monolayer of mouse stromal cells or animal tissue derived extracellular matrices. Generation of a 3-dimensional (3D) culture environment attempts to facilitate both cell-cell and cell-matrix interactions during iPSC differentiation. This study reports the development of a 3D culture system for hematopoietic differentiation of iPSCs to model TMD. iPSC colonies were encapsulated in 3D polyethylene glycol (PEG) based hydrogels containing synthetic integrin binding peptide (GRGDSPC) and enzymatically degradable peptide (GGPQGIWGQGKG) (Fig. 1A) and cultured in maintenance medium (mTeSR1™, Stem Cell Technology) without feeder cells. There were notable morphological differences between the 3D encapsulated and 2D cultured iPSC colonies (Fig. 1B). The 3D encapsulation did not have an adverse effect on the viability of the iPSC colonies evaluated by in situ staining with viability dye (Fig. 1C). The 3D encapsulated colonies were more compact with a spheroid morphology in PEG whereas colonies in 2D were more flattened (Fig. 1D). The pluripotency of the 3D encapsulated iPSCs was confirmed alkaline phosphatase staining (purple colonies) and by the presence of >96% population expressing pluripotency markers, Tra-1-60 and SSEA-4 (Fig. 1E). To test the efficiency of the 3D model system to generate HSPCs, the encapsulated iPSCs were subjected to hematopoietic differentiation using STEMdiff Hematopoietic Kit. Following differentiation, immunophenotype analysis of single cells by flow cytometry revealed a 1.7-fold higher CD34+CD45+CD38-CD45RA- cell percentage in 3D hydrogels compared to 2D. Further delineation of sub-populations in HSPC compartment from 2D and 3D hydrogel revealed a 1.9-fold and 2.1-fold higher population of early HSPCs and multipotent progenitors (MPPs) in 3D compared to 2D respectively (Fig 1F, *P<0.05). In colony forming unit (CFU) assay, the 3D generated HSPCs gave rise to a 2.0-fold higher number of CFU-GEMM (granulocyte, erythrocyte, monocyte, megakaryocyte) colonies compared to 2D, with 2.0-fold decreased number of BFU-E (erythroid) colonies and a similar number of CFU-GM (granulocyte, macrophage) colonies (Fig. 1G). Thus, the low modulus synthetic matrix promoted hematopoietic differentiation producing higher percentage of early HSPCs as compared to the 2D culture system. We used this 3D system to model TMD by utilizing isogenic iPSCs with disomy 21 (D21), trisomy 21 (T21), and trisomy 21 bearing pathologic mutation in GATA1 (T21-G1). The megakaryoid population in the HSPCs generated by hematopoietic differentiation of 3D encapsulated iPSCs was characterized by the percentage of CD34+CD41+ population within the total CD41+ population, myeloid population as CD18+CD45+ and erythroid population as CD71+CD235+. T21 HSPCs showed increased erythroid and megakaryoid populations as compared to isogenic D21, consistent with the role of trisomy 21 in perturbing hematopoiesis. T21-G1 had elevated megakaryoid (93±6% vs 71±1%,) and myeloid (32±16% vs 8±4%) populations with reduced erythroid (27±12% vs 79±6%) population as compared to T21 HSPCs implicating GATA1s in altered hematopoiesis (Fig. 1H). T21-G1 HSPCs only produced CFU-GM colonies as compared to a high number of CFU-GEMM and BFU-E in T21 and D21 HSPCs (Fig. 1I). The expression of GATA1s in T21-G1 megakaryoid population was confirmed (Fig. 1J). The immunophenotype marker analysis of T21-G1 megakaryoid blasts showed expression of megakaryoid/erythroid antigens (CD41, CD61, CD42b, CD71) along with myeloid markers (CD11b, CD33, CD13) and increased expression of CD56 and CD117 consistent with TMD patients (Fig. 1K). In conclusion, our cost-effective tunable 3D hydrogel system promoted hematopoietic differentiation of iPSCs and generated TMD model mimicking the salient features of the disease. Figure 1 Figure 1. Disclosures Barwe: Prelude Therapeutics: Research Funding. Gopalakrishnapillai: Geron: Research Funding.

BONE MARROW PROFILE IN HEMATOLOGICAL DISORDERS IN YEMENI PATIENS

There is paucity of information about the prevalence of hematological disorders in Yemen and neighboring countries .This is the rst project to evaluate the relative spectrum of hematological diseases in Taiz and Ibb governorate Yemen ,by method of bone marrow examination which is considered an important valuable diagnostic tool, for evaluation and nal diagnosis of various hematological and non-hematological disorders especially when CBC and peripheral blood lm study and other investigation failed to give a diagnosis . OBJECTIVES: The aim of this study was to evaluate the spectrum of haematological diseases diagnosed by bone marrow examination in Taiz and IBB governorates Yemen between September 2016 and October 2020 .Patients and method : A total of 1108 patients aged between (1 -100 )years old were evaluated by bone marrow examination at referral hematological center in IBB city Yemen . Relevant investigations were performed when needed. After exclusion of 98 patients with normal bone marrow ndings ,a total of 1010 patients had hematological disorders , and their data were analyzed. There were 527 (52.2 %) males and 483(47.8 %) females . A total of 655(64.9%) patients had benign hematological diseases and 355 (35.1% ) patients had malignant hematological diseases . RESULTS :A total of 138 patients had Iron deciency anemia ,107 had immune thrombocytopenic purpura (ITP) , 92 had hypersplenism,84 had Acute lymphoblastic leukemia ,79 had Acute myeloid leukaemia, 71 had megaloblastic anemia 58 had myeloproliferative disorder , 53 had Chronic myeloid leukemia , 45 had hemolytic anemia ,45had visceral leishmaniasis. 44 had malaria, 38 had chronic lymphocytic leukemia 38 had anemia of chronic disease ,25 had aplastic anemia ,25 had myelodysplastic syndromes, ,21 had anemia of infection ,19 had congenital syndroms,7had multiple myeloma ,6 had mixed deciency anemia and 5 had metastatic deposits , 4 had myeloid leukomoid reaction ,4 had lymphoma inltration and 2 had hairy cell leukemia . Sex- and age-related distribution of the various disorders was also presented. CONCLUSION: The anemias of all types were the most frequently encountered diagnosis followed by acute and chronic leukemias , ITP , Hypersplenism , ,myeloproliferative disorder , visceral leishmaniasis , malaria, myelodysplastic syndrome and congenital syndromes respectively. The other haematological disorders were less common. These ndings are comparable with published data in previous studies done in Yemen and other developing countries

Leukemic retinopathy, a rare entity: A case report

Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate. Consequently, the peripheral blood cell profile shows an increased number of granulocytes and their immature precursors, including occasional blast cells. CML accounts for 20% of all leukemias affecting adults. Retinal lesions are the most common ocular manifestation of leukemia. They are found most often in adults and in patients with myeloid leukemia. Despite the significant efforts made by different groups to optimize treatment and outcome, there are still unmet needs and unanswered questions. Ophthalmologic manifestations are among the therapeutic challenge. Here we present a case of CML (chronic phase) with ophthalmologic manifestations as initial presentation, trying to shed light on this important type of presentation.

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.

Dermatofibrosarcoma Protuberans and Chronic Myeloid Leukemia: A Rare Co-incidence

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, low grade, malignant fibroblastic tumor. Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by dysregulated production of granulocytic cell line without the loss of their capacity to differentiate. To our knowledge, there is no described association of DFSP with CML in literature. The authors have encountered a first case of DFSP coexisting with chronic myeloid leukemia.

Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm

<b><i>Introduction:</i></b> In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. <b><i>Methods:</i></b> This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. <b><i>Results:</i></b> Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41–54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. <i>JAK2</i>V617F was present in 10 subjects and <i>CALR</i> mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40–160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5–4.0) and 5.0 events (4.6–5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. <b><i>Conclusion:</i></b> Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.

Lysozyme nephropathy: A rare and reversible cause of acute kidney injury in chronic myelomonocytic leukemia

Acute kidney injury is a common complication in patients with hematological malignancies. The following is a brief description of a patient with a known myeloproliferative disorder that progressed to chronic myelomonocytic leukemia with a reversible acute kidney injury.