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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.
Leukemia 2005 Jun
PMID:Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations. 1584 27

Urokinase-type plasminogen activator (uPA) is a multifunctional extracellular serine protease implicated in different events including fibrinolysis, tissue remodeling, and hematopoiesis. The human uPA gene contains a major promoter region at around 2000 bp upstream from the transcription start site (+1), and a second regulatory region spanning nucleotides -90/+32 within the proximal promoter. Here, an inspection of this region revealed a novel 13-bp palindrome residing at position +8/+20. Interestingly, the palindrome contains the DNA consensus-binding hexamer for the RUNX/AML family of transcription factors that play a role in hematopoiesis, leukemia, and several developmental processes. Measuring the expression for promoter-reporter constructs after transfection revealed that deletion of the palindrome abrogated most of the proximal promoter activity in 293A cell. Additionally, electrophoretic mobility shift assays have shown that the palindrome could bind the RUNX1 component in nuclear extracts of myeloid cell lines exclusively through its RUNX motif. The palindrome was found in five additional human genes, two of which (MYH11 and MLLT1) have been linked to chromosomal rearrangements leading to leukemia. The data presented here have implicated, for the first time, RUNX/AML in the regulation of the uPA gene. The significance of the novel palindrome regarding gene regulation through the RUNX motif deserves further investigation.
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PMID:A RUNX/AML-binding motif residing in a novel 13-bp DNA palindrome may determine the expression of the proximal promoter of the human uPA gene. 1610 12

Over the last decade molecular diagnostics technology has developed dramatically from the most laborious, time- consuming southern blot methodology through the revolution of polymerase chain reaction PCR technology to the most reliable, fast, and contamination free molecular analyzer, the real-time quantitative-PCR. The Section of Hematology, Department of Pathology and Laboratory Medicine at King Faisal Specialist Hospital and Research Center has shared this experience during the last 10 years with more than 6,546 samples submitted for the analysis of different gene rearrangements, fusion gene transcripts and gene mutations including Ig heavy chain gene rearrangement for B-cell malignancies, T-cell receptor gamma chain gene rearrangement for T-cell malignancies, BCR/ABL-P210 and P190 fusion gene transcripts, for chronic myeloid leukemia and Philadelphia positive acute lymphoblastic leukemia, PML/RARalpha fusion gene for promyelocytic leukemia, AML1/ETO for acute myeloid leukemia AML-M2 with t8;21, CBFB/MYH11 for AML M4E0 with inv 16, BCL-2 for follicular lymphoma, and BCL-1 for mantle cell lymphoma. Hence, most molecular assays are qualitative in nature, quantitative assays are deemed necessary in the monitoring and follow-up of minimal residual disease in leukemia and lymphoma, and proved in our experience to serve as an essential tool to confirm complete remission CR post-chemotherapy and bone marrow transplantation, and to detect signs of early relapse for proper clinical intervention. In this manuscript, we retrospectively review our experience in molecular hematology and propose our recommended guidelines at King Faisal Specialist Hospital and Research Center.
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PMID:Molecular hematology. Qualitative to quantitative techniques. 1622 48

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.
Leukemia 2006 Jan
PMID:Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]. 1628 Oct 71

The acute myeloid leukemia (AML)-associated CBF beta-SMMHC fusion protein impairs hematopoietic differentiation and predisposes to leukemic transformation. The mechanism of leukemia progression, however, is poorly understood. In this study, we report a conditional Cbfb-MYH11 knockin mouse model that develops AML with a median latency of 5 months. Cbf beta-SMMHC expression reduced the multilineage repopulation capacity of hematopoietic stem cells (HSCs) while maintaining their numbers under competitive conditions. The fusion protein induced abnormal myeloid progenitors (AMPs) with limited proliferative potential but leukemic predisposition similar to that of HSCs in transplanted mice. In addition, Cbf beta-SMMHC blocked megakaryocytic maturation at the CFU-Meg to megakaryocyte transition. These data show that a leukemia oncoprotein can inhibit differentiation and proliferation while not affecting the maintenance of long-term HSCs.
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PMID:Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. 1641 72

The t(16:16) and inv(16) are associated with FAB M4Eo myeloid leukemias and result in fusion of the CBFB gene to the MYH11 gene (encoding smooth muscle myosin heavy chain [SMMHC]). Knockout of CBFbeta causes embryonic lethality due to lack of definitive hematopoiesis. Although knock-in of CBFB-MYH11 is not sufficient to cause disease, expression increases the incidence of leukemia when combined with cooperating events. Although mouse models are valuable tools in the study of leukemogenesis, little is known about the contribution of CBFbeta-SMMHC to human hematopoietic stem and progenitor cell self-renewal. We introduced the CBFbeta-MYH11 cDNA into human CD34+ cells via retroviral transduction. Transduced cells displayed an initial repression of progenitor activity but eventually dominated the culture, resulting in the proliferation of clonal populations for up to 7 months. Long-term cultures displayed a myelomonocytic morphology while retaining multilineage progenitor activity and engraftment in NOD/SCID-B2M-/- mice. Progenitor cells from long-term cultures showed altered expression of genes defining inv(16) identified in microarray studies of human patient samples. This system will be useful in examining the effects of CBFbeta-SMMHC on gene expression in the human preleukemic cell, in characterizing the effect of this oncogene on human stem cell biology, and in defining its contribution to the development of leukemia.
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PMID:Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. 1667 Feb 69

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinicobiological features. This translocation leads to fusion of MYST3 (MOZ) and CREBBP (CBP) genes, probably resulting in a disturbed transcriptional program of a myelomonocytic precursor. Nonetheless, its gene expression profile is unknown. We have analyzed the gene expression profile of 23 AML patients, including three with molecularly confirmed MYST3-CREBBP fusion gene, using oligonucleotide U133A arrays (Affymetrix). MYST3-CREBBP cases clustered together and clearly differentiated from samples with PML-RARalpha, RUNX1-RUNX1T1, and CBFbeta-MYH11 rearrangements. The relative expression of 46 genes, selected according to their differential expression in the high-density array study, was analyzed by low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP AML cases. Thus, genes such as prolactin (PRL) and proto-oncogene RET were confirmed to be specifically overexpressed in MYST3-CREBBP samples whereas genes such as CCND2, STAT5A, and STAT5B were differentially underexpressed in this AML category. Interestingly, MYST3-CREBBP AML exhibited a characteristic pattern of HOX expression, with up-regulation of HOXA9, HOXA10, and cofactor MEIS1 and marked down-regulation of other homeobox genes. This profile, with overexpression of FLT3, HOXA9, MEIS1, AKR7A2, CHD3, and APBA2, partially resembles that of AML with MLL rearrangement. In summary, this study shows the distinctive gene expression profile of MYST3-CREBBP AML, with overexpression of RET and PRL and a specific pattern of HOX gene expression.
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PMID:Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. 1684 38

Human acute myeloid leukaemia (AML) involving a core-binding factor (CBF) transcription factor is called CBF leukaemia. In these leukaemias, AML1 (RUNX1, PEBP2alphaB, CBFalpha2)-MTG8 (ETO) and CBFbeta (PEBP2beta)-MYH11 chimaeric proteins are generated by t(8;21) and inv(16) respectively. We analysed gene expression profiles of leukaemic cells by microarray, and selected genes whose expression appeared to be modulated in association with t(8;21) and inv(16). In a pair-wise comparison, 15% of t(8;21)-associated transcripts exhibited high or low expression in inv(16)-AML, and 26% of inv(16)-associated transcripts did so equivalently in t(8;21)-AML. These common elements in gene expression profiles between t(8;21)- and inv(16)-AML probably reflect the situation that AML1-MTG8 and CBFbeta-MYH11 chimaeric proteins affect a common set of target genes in CBF leukaemic cells. On the other hand, 38% of t(8;21)-associated and 24% of inv(16)-associated transcripts were regulated in t(8;21)- and inv(16)-specific manners. These distinct features of t(8;21)- and inv(16)-associated genes correlate with the bimodular structures of the chimaeric proteins (CBF-related AML1 and CBFbeta portions, and CBF-unrelated MTG8 and MYH11 portions).
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PMID:Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukaemia. 1698 59

The spectrum of CBFB-MYH11 fusion transcripts in acute myeloid leukemia (AML) M4eo with inv(16)/t(16;16) is heterogeneous. Approximately 85% show type A CBFB-MYH11 fusion transcripts. In addition, more than 10 different fusion transcripts have been reported. The prognostic impact and biological background of rare fusion transcripts remain open. In this study, a molecular characterization of CBFB-MYH11 transcripts in 162 patients with CBFB-MYH11 positive AML at diagnosis was performed. In total, 128 patients (79.0%) showed the fusion transcript type A, whereas nine different rare CBFB-MYH11 fusion genes were detected in 34 cases (21.0%). Rare fusion transcripts were found more frequently in therapy-related AML (P=0.0106). Numerical gains of the chromosomes 8, 21 and 22 were more frequently associated with type A (28.3%) than with rare fusions (12.9%) (P=0.012). Median white blood cell (WBC) count was higher in type A (35.4 G/l; range=1.1-279 G/l) than in cases with rare types (7.8 G/l; range=0.8-148.0 G/l) (P<0.0001). Rare fusion transcripts were correlated with an atypical cytomorphology not primarily suggestive for the FAB subtype M4eo (P=0.0203). Immunophenotype revealed lower CD2, CD13, CD33 and CD90 levels than in type A fusion cases (P=0.036, 0.002, 0.029 and 0.045, respectively). However, the type of fusion was not an independent prognostic parameter.
Leukemia 2007 Apr
PMID:Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients. 1728 58

Acute myeloid leukemia with inv(16)(p13q22), also known as M4Eo, is a distinct type of leukemia with characteristic clinicopathologic and cytogenetic features. Patients with M4Eo have monocytosis, high blast counts, and abnormal bone marrow eosinophils that contain large basophilic granules. The inv(16)(p13q22) or, less commonly, the t(16;16)(p13;q22) causes fusion of the CBFbeta gene at 16q22 and the MYH11 gene at 16p13, creating the novel chimeric protein CBFbeta-MYH11. To understand the underlying molecular mechanisms unique to M4Eo biology, we determined the gene expression profile of M4Eo cases by using cDNA and long oligonucleotide microarrays. Cases of acute myelomonocytic leukemia without CBFbeta-MYH11 (M4) acted as our control. We found that in the gene expression profile of M4Eo, NF-kappaB activators and inhibitors were upregulated and downregulated, respectively, suggesting that the NF-kappaB signaling pathway is activated at a higher level in M4Eo than in acute myelomonocytic leukemia M4. In addition, the gene expression profile of M4Eo indicates high cell proliferation and low apoptosis. We used real-time PCR, immunohistochemistry, and flow cytometry immunophenotyping to confirm some of our microarray data. These findings most likely represent the functional consequences of the abnormal chimeric protein CBFbeta-MYH11, which is unique to this disease, and suggest that NF-kappaB is a potential therapeutic target for treating M4Eo patients.
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PMID:Comparative analysis of genes regulated in acute myelomonocytic leukemia with and without inv(16)(p13q22) using microarray techniques, real-time PCR, immunohistochemistry, and flow cytometry immunophenotyping. 1757 Oct 80


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