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Michael L Cleary - One of the best experts on this subject based on the ideXlab platform.
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the menin tumor suppressor protein is an essential oncogenic cofactor for mll associated leukemogenesis
2005Co-Authors: Akihiko Yokoyama, Orit Rozenblattrosen, Matthew Meyerson, Tim C P Somervaille, Kevin S Smith, Michael L ClearyAbstract:The Mixed-Lineage Leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors. We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis. Furthermore, menin is essential for maintenance of MLL-associated but not other oncogene induced Myeloid Transformation. Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers.
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binding to nonmethylated cpg dna is essential for target recognition transactivation and Myeloid Transformation by an mll oncoprotein
2004Co-Authors: Paul M Ayton, Everett H Chen, Michael L ClearyAbstract:The MLL gene is a frequent target for leukemia-associated chromosomal translocations that generate dominant-acting chimeric oncoproteins. These invariably contain the amino-terminal 1,400 residues of MLL fused with one of a variety of over 30 distinct nuclear or cytoplasmic partner proteins. Despite the consistent inclusion of the MLL amino-terminal region in leukemia oncoproteins, little is known regarding its molecular contributions to MLL-dependent oncogenesis. Using high-resolution mutagenesis, we identified three MLL domains that are essential for in vitro Myeloid Transformation via mechanisms that do not compromise subnuclear localization. These include the CXXC/Basic domain and two novel domains of unknown function. Point mutations in the CXXC domain that eliminate Myeloid Transformation by an MLL fusion protein also abolished recognition and binding of nonmethylated CpG DNA sites in vitro and transactivation in vivo. Our results define a critical role for the CXXC DNA binding domain in MLL-associated oncogenesis, most likely via epigenetic recognition of CpG DNA sites within the regulatory elements of target genes.
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Transformation of Myeloid progenitors by mll oncoproteins is dependent on hoxa7 and hoxa9
2003Co-Authors: Paul M Ayton, Michael L ClearyAbstract:Transcriptional deregulation through the production of dominant-acting chimeric transcription factors derived from chromosomal translocations is a common theme in the pathogenesis of acute leukemias; however, the essential target genes for acute leukemogenesis are unknown. We demonstrate here that primary Myeloid progenitors immortalized by various MLL oncoproteins exhibit a characteristic Hoxa gene cluster expression profile, which reflects that preferentially expressed in the Myeloid clonogenic progenitor fraction of normal bone marrow. Continued maintenance of this MLL-dependent Hoxa gene expression profile is associated with conditional MLL-associated Myeloid immortalization. Moreover, Hoxa7 and Hoxa9 were specifically required for efficient in vitro Myeloid immortalization by an MLL fusion protein but not other leukemogenic fusion proteins. Finally, in a bone marrow transduction/transplantation model, Hoxa9 is essential for MLL-dependent leukemogenesis in vivo, a primary requirement detected at the earliest stages of disease initiation. Thus, a genetic reliance on Hoxa7 and Hoxa9 in MLL-mediated Transformation demonstrates a gain-of-function mechanism for MLL oncoproteins as upstream constitutive activators that promote Myeloid Transformation via a Hox-dependent mechanism.
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HoxA9-mediated immortalization of Myeloid progenitors requires functional interactions with TALE cofactors Pbx and Meis.
2000Co-Authors: Catherine A. Schnabel, Yakop Jacobs, Michael L ClearyAbstract:Specific Hox genes are implicated in leukemic Transformation, and their selective genetic collaboration with TALE homeobox genes, Pbx and Meis, accentuates their oncogenic potential. The molecular mechanisms underlying these coordinate functions, however, have not been characterized. In this study, we demonstrate that HoxA9 requires its Pbx interaction motif as well as its amino terminus to enhance the clonogenic potential of Myeloid progenitors in vitro. We further show that HoxA9 forms functional trimeric DNA binding complexes with Pbx and Meis-like proteins on a modified enhancer. DNA binding complexes containing HoxA9 and TALE homeoproteins display cooperative transcriptional activity and are present in leukemic cells. Trimeric complex formation on its own, however, is not sufficient for HoxA9-mediated immortalization. Rather, structure-function analyses demonstrate that domains of HoxA9 which are necessary for cellular Transformation are coincident with those required for trimer-mediated transcriptional activation. Furthermore, the amino terminus of HoxA9 provides essential transcriptional effector properties and its requirement for Myeloid Transformation can be functionally replaced by the VP16 activation domain. These data suggest that biochemical interactions between HoxA9 and TALE homeoproteins mediate cellular Transformation in hematopoietic cells, and that their transcriptional activity in higher order DNA binding complexes provides a molecular basis for their collaborative roles in leukemogenesis.
Melvin H Freedman - One of the best experts on this subject based on the ideXlab platform.
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clonal evolution in marrows of patients with shwachman diamond syndrome a prospective 5 year follow up study
2002Co-Authors: Yigal Dror, Peter R. Durie, Hedy Ginzberg, Rebecca Herman, Anu Banerjee, Martin Champagne, Kevin Shannon, David Malkin, Melvin H FreedmanAbstract:Abstract Objectives Shwachman-Diamond syndrome (SDS) is characterized by varying degrees of marrow failure. Retrospective studies suggested a high propensity for malignant Myeloid Transformation into myelodysplastic syndromes (MDS) and acute Myeloid leukemia (AML). The study's aims were to determine the cellular and molecular characteristics as well as the clinical course of malignant Myeloid Transformation and clonal marrow disease in patients with SDS. Methods This is a longitudinal prospective study of 14 patients recruited for annual hematological evaluations. Results of baseline and serial hematological assessments for up to 5 years are reported. Results Clonal marrow cytogenetic abnormalities (CMCA) were detected in 4 patients (29%) on first testing or at follow-up. The abnormalities were del(20q) in two patients, i(7q) in one, and combined del(20q) and i(7q) in one. The following tests did not distinguish patients with CMCA from other SDS patients: severity of peripheral cytopenia, fetal hemoglobin levels, percentage of marrow CD34 + cells, colony growth from marrow CD34 + cells, cluster-to-colony ratio, marrow stromal function, percentage of marrow apoptosis cells, and granulocyte colony-stimulating factor receptor expression. RAS and p53 mutation analysis and AML blast colony assays were uniformly negative. No patients showed progression into more advanced stages of MDS or into AML. In one patient, the abnormal clone became undetectable after 2 years of follow-up. Conclusions We conclude that although CMCA in SDS is high, progression into advanced stages of MDS or to overt AML may be slow and difficult to predict. Treatment should be cautious since some abnormal clones can regress.
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shwachman diamond syndrome an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment
1999Co-Authors: Yigal Dror, Melvin H FreedmanAbstract:Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant Myeloid Transformation, is an important model for understanding genetic determinants in hematopoiesis. To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34(+) cells on bone marrow aspirates. SD CD34(+) cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34(+) cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34(+) cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.
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Malignant Myeloid Transformation with isochromosome 7q in Shwachman-Diamond syndrome.
1998Co-Authors: Yigal Dror, J Squire, Peter R. Durie, Melvin H FreedmanAbstract:Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, various degrees of cytopenia, and a striking tendency to develop myelodysplastic syndrome and acute myeloblastic leukemia. Isochromosome 7 [i(7q)] is a rare non-random cytogenetic abnormality of Myeloid cells in hematological malignancy. We report two cases of Shwachman-Diamond syndrome in which patients developed myelodysplastic syndrome and i(7q), detected by G-banding karyotype analysis and fluorescence in situ hybridization. Three other children have been previously reported to have myelodysplastic syndrome in association with i(7q); two of them had Shwachman-Diamond syndrome. Isochromosome 7q may be a fairly specific marker of Myeloid malignant Transformation in this syndrome and play a role in its pathogenesis.
Josee Brossard - One of the best experts on this subject based on the ideXlab platform.
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The impact of category, cytopathology and cytogenetics on development and progression of clonal and malignant Myeloid Transformation in inherited bone marrow failure syndromes
2015Co-Authors: Michaela Cada, Catherin I. Segbefia, Robert J. Klaassen, Conrad V. Fernandez, Rochelle Yanofsky, Yves D. Pastore, Mariana Silva, Jeffrey H. Lipton, Josee BrossardAbstract:Inherited bone marrow failure syndromes are a group of rare, heterogeneous genetic disorders with a risk of clonal and malignant Myeloid Transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome and acute Myeloid leukemia. The clinical characteristics, risk classification, prognostic factors and outcome of clonal and malignant Myeloid Transformation associated with inherited bone marrow failure syndromes are largely unknown. The aims of this study were to determine the impact of category, cytopathology and cytogenetics, the three components of the “Category Cytology Cytogenetics” classification of pediatric myelodysplastic syndrome, on the outcome of clonal and malignant Myeloid Transformation associated with inherited bone marrow failure. We used data from the Canadian Inherited Marrow Failure Registry. Among 327 patients with inherited bone marrow failure syndrome enrolled in the registry, the estimated risk of clonal and malignant Myeloid Transformation by the age of 18 years was 37%. The risk of clonal and malignant Myeloid Transformation varied according to the type of inherited bone marrow failure syndrome but was highest in Fanconi anemia. The development of clonal and malignant Myeloid Transformation significantly affected overall survival. Mortality varied based on cytopathological group. The largest group of patients had refractory cytopenia. Clonal marrow cytogenetic abnormalities were identified in 87% of patients with clonal and malignant Myeloid Transformation, and different cytogenetic groups had different impacts on disease progression. We conclude that category, cytopathology and cytogenetics in cases of clonal and malignant Myeloid Transformation associated with inherited bone marrow failure syndromes have an important impact on outcome and that the classification of such cases should incorporate these factors.
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outcome and clinical characteristics of clonal and malignant Myeloid Transformation in inherited bone marrow failure syndromes
2012Co-Authors: Michaela Cada, Catherin I. Segbefia, Robert J. Klaassen, Conrad V. Fernandez, Rochelle Yanofsky, Mariana Silva, Jeffrey H. Lipton, Josee Brossard, Josette Champagne, Yvan SamsonAbstract:Abstract 1266 Introduction: Inherited bone marrow failure syndromes (IBMFSs) are a group of rare, genetic disorders with a risk of clonal and malignant Myeloid Transformation including clonal marrow cytogenetic abnormalities, myelodysplastic syndrome (MDS) and acute Myeloid leukemia (AML). The clinical characteristics and outcome of IBMFS-related clonal and malignant Myeloid Transformation are unclear, particularly in cases of early Transformation such as isolated clonal marrow cytogenetic abnormalities. Objectives: The aims of this study were to determine the risk and clinical outcome of IBMFS-related clonal and malignant Myeloid Transformation using data from the Canadian Inherited Marrow Failure Registry (CIMFR). Methods: The CIMFR is a multicenter collaborative study which is intended to enroll all patients with IBMFSs in Canada. The registry was approved by the Institutional Ethics Board of all the participating institutions, and includes 15 of 16 pediatric tertiary care centers across all provinces in Canada. We estimate that these centers care for >95% of the eligible pediatric IBMFS population in Canada. The CIMFR is population-based as >90% of the patients in this study are from centers who enrolled >80% of the patients in their institutions. Clonal and malignant Myeloid Transformation was defined as having either clonal marrow cytogenetic abnormalities or prominent bi-lineage morphologic dysplasia or increased percentage of marrow blasts (≥5%) or a combination of the above. Results: Among 327 IBMFS patients enrolled on the CIMFR, 45 (13.8%) developed clonal and malignant Myeloid Transformation. In these 45 patients, the three most common IBMFS diagnoses were Fanconi anemia (31.1%), Shwachman-Diamond syndrome (20.0%) and unclassifiable IBMFSs (28.9%). Clonal marrow cytogenetic abnormalities were identified in 38/45 (84.4%) patients, while 5/45 (11.1%) patients had constitutional cytogenetic changes, 1/45 patients had AML with no cytogenetic abnormalities and 1/45 patients had no cytogenetic abnormalities. Two out of the 5 patients with constitutional cytogenetic abnormalities developed a clonal marrow cytogenetic abnormality later in their disease course. The most common clonal marrow cytogenetic abnormality was monosomy 7, which was found in 14/38 (36.8%) patients. Cytology in the majority of patients 20/45 (44.4%) was consistent with refractory cytopenia. Eight out of the 45 patients developed AML and 2 of these patients had monosomy 7. Twenty-two out of 45 (48.9%) patients with clonal and malignant Myeloid Transformation underwent hematopoietic stem cell transplantation due to severe cytopenia, excess blasts or leukemia. Fourteen out of the 22 (63.6%) transplanted patients are alive at last follow-up. Out of 8 patients who had AML, 3 received transplant and are alive at last follow-up. The 5 remaining AML patients died; 3 while awaiting transplant, 1 did not achieve remission and 1 refused transplant. Overall mortality in the group of patients with clonal and malignant Myeloid Transformation was 15/45 (33.3%) at a median follow-up of 10 months from diagnosis with clonal and malignant Myeloid Transformation. Overall mortality in those 282 patients on CIMFR without clonal and malignant Myeloid Transformation is 6.4%. Conclusion: Despite short-term follow-up of patients on the CIMFR, a relatively high prevalence of clonal and malignant Myeloid Transformation was found. Clonal marrow cytogenetic abnormalities are associated with a high risk of progression into advanced MDS or AML and death. Disclosures: No relevant conflicts of interest to declare.
Hiroyoshi Kunimoto - One of the best experts on this subject based on the ideXlab platform.
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cooperative epigenetic remodeling by tet2 loss and nras mutation drives Myeloid Transformation and mek inhibitor sensitivity
2018Co-Authors: Hiroyoshi Kunimoto, Cem Meydan, Kaitlyn Shank, Abbas Nazir, Justin T Whitfield, Franck Rapaport, Rebecca Maher, Elodie Pronier, Sara C Meyer, Francine E GarrettbakelmanAbstract:Summary Mutations in epigenetic modifiers and signaling factors often co-occur in Myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and Nras G12D expression in hematopoietic cells induced Myeloid Transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in Myeloid Transformation and provide a rationale for mechanism-based therapy in CMML patients with these high-risk genetic lesions.
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cooperative epigenetic remodeling by tet2 loss and nras mutation drives Myeloid Transformation and mek inhibitor sensitivity
2016Co-Authors: Hiroyoshi Kunimoto, Cem Meydan, Kaitlyn Shank, Abbas Nazir, Franck Rapaport, Rebecca Maher, Elodie Pronier, Ari Melnick, Ross L Levine, Alan H. ShihAbstract:Abstract Epigenetic modifiers and signaling factors are frequently mutated and often co-occur in various Myeloid malignancies. However, precisely how these mutations cooperate to cause Myeloid leukemia is not fully understood. Here, we show that cells with concurrent Ten-eleven-translocation 2 (Tet2) loss and Nras mutation can cause lethal chronic myelomonocytic leukemia (CMML) like disease in vivo and synergistically activate Ras signaling through epigenetic silencing of Sprouty 2 (Spry2), thereby making cells with both disease alleles dependent on MAPK signaling and highly sensitive to MEK inhibition. To assess if Tet2 loss and Nras mutation cooperate in Myeloid Transformation, we crossed Tet2 conditional knockout mice (Mx1-Cre+ Tet2f/f) and Nras mutant mice (Mx1-Cre+ Nras+/G12D) to generate Mx1-Cre+ Tet2f/f Nras+/G12D mice (Tet2Δ/Δ Nras+/G12D). These mice, compared to single mutant mice with either allele alone, had more significant monocytosis, expansion of Lineage- Sca-1+ c-Kit+ (LSK) and Myeloid progenitors in both bone marrow (BM) and spleen and development of lethal CMML-like disease (median survival 264 days). Moreover, serial transplantation of splenic cells derived from leukemic Tet2Δ/Δ Nras+/G12D mice caused similar CMML-like disease in recipients, which emanates from LSK-positive stem/progenitor cells as the disease propagating population. To delineate how Tet2 loss and Nras mutation synergize in leukemic Transformation, we next performed western blot and phospho-flow analysis of MAPK and PI3K signaling in primary hematopoietic cells. Interestingly, pErk, pAkt and pS6 expression were significantly higher in Tet2Δ/Δ Nras+/G12D cells compared to WT or single mutant cells, indicating that Tet2 loss and Nras mutation cooperates to further activate Ras signaling (Figure 1). Consistent with our murine model, TET2 silencing in NRAS mutant human leukemia cells increased MAPK output, consistent with augmentation of signaling by concurrent TET2/NRAS alterations in human leukemia cells. To unravel the molecular mechanism of Ras signaling activation, we assessed mRNA / protein expression and performed bisulfite sequencing of known regulators of MAPK signaling, including Sprouty family members. We observed significant decrease of Spry2 expression, stepwise and specific hyper-methylation of CpG islands in the Spry2 promoter region in Tet2Δ/Δ Nras+/G12D cells compared to WT or single mutant cells, consistent with progressive epigenetic remodeling in these leukemia cells in vivo (Figure 2). Genome wide methylation profiling of WT, single mutant and Tet2Δ/Δ Nras+/G12D LSK cells using enhanced reduced representation bisulfite sequencing demonstrated clear separation of leukemic Tet2Δ/Δ Nras+/G12D LSKs from WT or single mutant LSKs. Most importantly, restoration of Spry2 expression in Tet2Δ/Δ Nras+/G12D cells led to decrease in pErk / pAkt level and significantly reduced colony formation, which functionally validates Spry2 as a key epigenetic target in Tet2/Nras mutant leukemia cells. We next assessed whether the increased MAPK signaling seen in Tet2Δ/Δ Nras+/G12D cells leads to differential sensitivity to MEK inhibition by performing studies with the clinical MEK inhibitor binimetinib (ARRY162). Tet2Δ/Δ Nras+/G12D cells showed significantly higher sensitivity to binimetinib compared to Nras+/G12D cells in vitro (IC50, 6.948nM vs. 690.4nM). Moreover, in vivo treatment of Tet2Δ/Δ Nras+/G12D leukemic recipients with binimetinib restored splenomegaly, significantly reduced disease burden in BM and spleen and improved overall survival compared to vehicle treatment (median survival 24.5 days vs. 44.5 days, p=0.0018, Figure 3). Of note, knockdown of human TET2 in NRAS mutant human leukemia cells sensitized to MEK inhibition in a similar manner demonstrating this approach may have value in leukemia patients with concurrent TET2 and NRAS mutations. These data clearly indicate that Tet2 loss and Nras mutation synergize in Myeloid Transformation and cooperatively remodel DNA methylation, which leads to epigenetic silencing of Spry2 and synergistic activation of MAPK signaling, which can be leveraged through therapeutic MEK inhibition. Our studies provide novel insights into how signaling and epigenetic mutations cooperate in leukemic Transformation and provide a rationale for mechanism based therapy in CMML patients with these high risk genetic lesions. Download : Download high-res image (101KB) Download : Download full-size image Download : Download high-res image (203KB) Download : Download full-size image Download : Download high-res image (91KB) Download : Download full-size image Disclosures Melnick: Janssen: Research Funding. Levine: Qiagen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.
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genetic basis of Myeloid Transformation in familial platelet disorder acute Myeloid leukemia patients with haploinsufficient runx1 allele
2016Co-Authors: Masatoshi Sakurai, Hidenori Kasahara, Kenichi Yoshida, Akihide Yoshimi, Hiroyoshi Kunimoto, Naohide Watanabe, Yuichi Shiraishi, Kenichi Chiba, Hirotoshi Tanaka, Yuka HaradaAbstract:Genetic basis of Myeloid Transformation in familial platelet disorder/acute Myeloid leukemia patients with haploinsufficient RUNX1 allele
Yigal Dror - One of the best experts on this subject based on the ideXlab platform.
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clonal evolution in marrows of patients with shwachman diamond syndrome a prospective 5 year follow up study
2002Co-Authors: Yigal Dror, Peter R. Durie, Hedy Ginzberg, Rebecca Herman, Anu Banerjee, Martin Champagne, Kevin Shannon, David Malkin, Melvin H FreedmanAbstract:Abstract Objectives Shwachman-Diamond syndrome (SDS) is characterized by varying degrees of marrow failure. Retrospective studies suggested a high propensity for malignant Myeloid Transformation into myelodysplastic syndromes (MDS) and acute Myeloid leukemia (AML). The study's aims were to determine the cellular and molecular characteristics as well as the clinical course of malignant Myeloid Transformation and clonal marrow disease in patients with SDS. Methods This is a longitudinal prospective study of 14 patients recruited for annual hematological evaluations. Results of baseline and serial hematological assessments for up to 5 years are reported. Results Clonal marrow cytogenetic abnormalities (CMCA) were detected in 4 patients (29%) on first testing or at follow-up. The abnormalities were del(20q) in two patients, i(7q) in one, and combined del(20q) and i(7q) in one. The following tests did not distinguish patients with CMCA from other SDS patients: severity of peripheral cytopenia, fetal hemoglobin levels, percentage of marrow CD34 + cells, colony growth from marrow CD34 + cells, cluster-to-colony ratio, marrow stromal function, percentage of marrow apoptosis cells, and granulocyte colony-stimulating factor receptor expression. RAS and p53 mutation analysis and AML blast colony assays were uniformly negative. No patients showed progression into more advanced stages of MDS or into AML. In one patient, the abnormal clone became undetectable after 2 years of follow-up. Conclusions We conclude that although CMCA in SDS is high, progression into advanced stages of MDS or to overt AML may be slow and difficult to predict. Treatment should be cautious since some abnormal clones can regress.
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shwachman diamond syndrome an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment
1999Co-Authors: Yigal Dror, Melvin H FreedmanAbstract:Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant Myeloid Transformation, is an important model for understanding genetic determinants in hematopoiesis. To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34(+) cells on bone marrow aspirates. SD CD34(+) cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34(+) cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34(+) cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.
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Malignant Myeloid Transformation with isochromosome 7q in Shwachman-Diamond syndrome.
1998Co-Authors: Yigal Dror, J Squire, Peter R. Durie, Melvin H FreedmanAbstract:Shwachman-Diamond syndrome is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, bony metaphyseal dysostosis, various degrees of cytopenia, and a striking tendency to develop myelodysplastic syndrome and acute myeloblastic leukemia. Isochromosome 7 [i(7q)] is a rare non-random cytogenetic abnormality of Myeloid cells in hematological malignancy. We report two cases of Shwachman-Diamond syndrome in which patients developed myelodysplastic syndrome and i(7q), detected by G-banding karyotype analysis and fluorescence in situ hybridization. Three other children have been previously reported to have myelodysplastic syndrome in association with i(7q); two of them had Shwachman-Diamond syndrome. Isochromosome 7q may be a fairly specific marker of Myeloid malignant Transformation in this syndrome and play a role in its pathogenesis.
