Myeloid Leukemia with Myelodysplasia-Related Changes Was Not a Prognostic Factor Under Allogenic Hematopoietic Stem Cell Transplantation
Yoonha LeeTomoe IchikiMotohito OkabeYuka KawaguchiMarie OhbikiMasahide OsakiMiyo GotoTakahiko SatoHiroaki AraieTatsunori GotoTakanobu MorishitaYukiyasu OzawaKoichi Miyamura
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Introduction and Objectives Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is briefly defined as an AML which have multilineage dysplasia (MLD), a history of myelodysplastic syndrome (MDS) and/or an MDS-related cytogenetic abnormalities. Recent study showed that AML-MRC exhibits a worse clinical outcome than AML not otherwise specified (AML-NOS). Though allogenic hematopoietic stem cell transplantation (allo-SCT) is believed to improve the outcome of AML-MRC, few reports had referred to its benefit. The purpose of this study was to clarify the outcome and the prognostic factors of patients (pts) with AML-MRC who underwent allo-SCT. Methods Between January 2008 to December 2017, a total of 138 consecutive AML-MRC (n = 50) and AML-NOS (n = 88) pts who underwent allo-SCT in Japanese Red Cross Nagoya Daiichi Hospital were retrospectively analyzed. The classifications of diagnoses were made according to the criteria of the 2008 WHO classification and data of clinical, pathologic and cytogenetic features were collected. Results Among 138 pts, the median age at SCT was 45.5 years (range, 17 to 66 years), and 59 (43%) pts were female. Performance status was 2-4 for 7 (5%) pts and HCT-CI was ≧3 for 14 (10%) pts. The cytogenetic features were classified as intermediate risk for 78 (57%) pts and high or unknown risk for 60 (43%) pts according to the Southwest Oncology Group (SWOG) criteria. Ninety-five (69%) pts were in complete remission (CR) at SCT. Twenty-four (17%) pts had related donor and 71 (51%), 31 (22%), and 36 (26%) pts received bone marrow, peripheral blood stem cell, and cord blood, respectively. Myeloablative conditioning was performed in 87 (63%) pts. The median follow-up period for survivors was 51 months (range, 3 to 108 months). Compared to AML-NOS pts, pts with AML-MRC had significantly low frequency of CR at SCT (48% vs 81%, p Subgroup analysis was performed and SWOG high risk cytogenetics was identified as independent prognostic factor in the pts with AML-NOS (HR 2.31, p = 0.01). Among pts with AML-MRC, MDS-related cytogenetics (HR 4.52, p Conclusion Here we show that cytogenetic features, but not a diagnosis of AML-MRC, is one of the most important prognostic factors when performing allo-SCT,Since the early 1980s, developing haematopoietic cells have been categorised into three well-defined compartments: multi-potent haematopoietic stem cells (HSC), which are able to self-renew, followed by haematopoietic progenitor cells (HPC), which undergo decision-making and age as they divide rather than self-renew, and the final compartment of functional blood and immune cells. The classic model of haematopoiesis divides cells into two families, myeloid and lymphoid, and dictates a route to a particular cell fate. New discoveries question these long-held principles, including: (i) the identification of lineage-biased cells that self-renew; (ii) a strict myeloid/lymphoid dichotomy is refuted by the existence of progenitors with lymphoid potential and an incomplete set of myeloid potentials; (iii) there are multiple routes to some end cell types; and (iv) thymocyte progenitor cells that have progressed some way along this pathway retain clandestine myeloid options. In essence, the progeny of HSC are more versatile and the process of haematopoiesis is more flexible than previously thought. Here we examine this new way of viewing haematopoiesis and the impact of rewriting an account of haematopoiesis on our understanding of what goes awry in leukaemia.
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Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1–deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1−/− mice is normocellular histologically. However, Lin−Sca-1+c-Kit+ (LSK) cells are expanded in Tc1−/− mice compared to wild type controls. The expanded population mostly consists of CD150−CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1−/− mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1−/− mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.
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Flt3 ligand (Flt3L) is a growth factor for hemopoietic progenitors and can promote the expansion of both conventional dendritic cells (DCs) and plasmacytoid predendritic cells (p-preDCs). The cells responding to Flt3L treatment and the precursors for the DCs and p-preDCs had not been fully characterized. We examined different mouse bone marrow (BM) hemopoietic precursor populations for the surface expression of Flt3 and tested them for early DC and p-preDC precursor activity. Most DC precursor activity, other than that given by multipotent hemopoietic stem cells, was within the downstream precursors expressing Flt3. The majority of mouse BM common lymphoid precursors expressed high levels of Flt3 and these were the most efficient precursors of both DCs and p-preDCs. In contrast, only a small proportion of the common myeloid precursors (CMPs) expressed Flt3, but the precursor activity for both DCs and p-preDCs was within this minor Flt3+ CMP fraction. The granulocyte and macrophage precursors and pro-B cells did not express Flt3 and had no DC or p-preDC precursor activity. These findings demonstrate that the early precursors for all DC subtypes are within the BM Flt3+ precursor populations, regardless of their lymphoid or myeloid lineage orientation.
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Both acute myeloid leukemia 1 and c‐Fos are regulatory factors of hematopoietic cell differentiation. We identified that the c‐fos promoter contains an acute myeloid leukemia 1 binding site at nucleotide positions −6–+14. c‐fos promoter activity was induced by transient overexpression of acute myeloid leukemia 1 in Jurkat T‐cells, but not by that of the short form of acute myeloid leukemia 1‐MTG8, a chimeric acute myeloid leukemia 1 protein. In 32Dcl3 myeloid cells, stable overexpression of acute myeloid leukemia 1‐MTG8 blocked the c‐fos gene transcription and cell differentiation, but that of acute myeloid leukemia did not. These data suggest that acute myeloid leukemia 1 and acute myeloid leukemia 1‐MTG8 reciprocally regulate the myeloid cell differentiation, possibly by the way of regulating c‐fos gene transcription.
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PU.1 is a member of the Ets transcription family and is predominantly expressed in haematopoietic cells such as myeloid cells and B lymphoid cells.PU.1 regulates the expression of a number of myeloid gene and the haematopoietic differentiation.The disruption of PU.1 function is involved in acute myeloid leukemia.
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PU.1 is a member of the Ets transcription family and is predominantly expressed in haematopoietic cells such as myeloid cells and B lymphoid cells. PU.1 regulates the expression of a number of myeloid gene and the haematopoietic differentiation. The disruption of PU.1 function is involved in acute myeloid leukemia.
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Morphologic analysis of hemopoietic tissue in mouse liver reveals the persistence of erythropoietic, granulopoietic, and lymphopoietic activity for approximately 2 wk after birth. Near the end of the first postnatal week, we noted a remarkable reorganization of the hemopoietic cells that was characterized by a transition from a diffuse distribution of mixed erythroid, myeloid, and lymphoid elements to a focal pattern of discrete hemopoietic colonies scattered among the cords of hepatic parenchymal cells. Each hemopoietic focus contained cells progressing along a single differentiation pathway (i.e., erythroid, myeloid, or lymphoid cells). Megakaryocytes were seen as solitary cells surrounded by hepatocytes. This pattern of colonization was observed in all strains of mice examined. In the livers of mice with known hemopoietic defects, however, differences were found in the duration of postnatal hemopoiesis. Accessory cells with macrophage-like features were consistently observed in erythropoietic foci, but were rarely seen in lymphoid foci. The latter were formed by pre-B cells identifiable by the presence of cytoplasmic mu-heavy chains and the absence of light chain expression. The occurrence of discrete colonies of erythroid, myeloid, and pre-B lymphoid cells in the postnatal liver suggests that each is derived from a single, committed precursor cell. This anatomical compartmentalization according to cell type offers a useful model system for analysis of hemopoietic differentiation and of the generation of clonal diversity among B lineage cells.
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