Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia.

Weatherall, D. J.; Edwards, John A.; Donohoe, W. T. A.

doi:10.1136/bmj.1.5593.679

Cited by 104 publications

(38 citation statements)

References 13 publications

(20 reference statements)

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“…The deficiency in synthesis of ; chains can be seen in Fig. 3 (27). On the other hand, there is recent evidence of a relationship between fetal hemoglobin synthesis in erythroid colonies for normal adult erythrocyte progenitors and the degree of maturity of the precursors from which they are derived (28).…”

mentioning

confidence: 96%

Embryonic erythroid differentiation in the human leukemic cell line K562.

Rutherford¹,

Clegg²,

Higgs³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

162

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K562 human leukemia cells synthesize embryonic hemoglobins after culture in the presence ofhemin. We have rigorously identified these hemoglobins by globin chain analysis and peptide mapping. No adult hemoglobin could be detected, and (3-globin synthesis was less than 2 ppm of total protein synthesis. Persistent embryonic globin gene expression is known to occur as a consequence of globin gene deletions. However, restriction endonuclease mapping showed that the globin gene complexes in K562 cells are indistinguishable from normal. Hemin increased the rate ofembryonicglobin synthesis. The pattern ofhemoglobin synthesis proved to be stable when cells from different laboratories were compared. One line, however, synthesized large amounts ofHb X and very little Hb Portland in response to hemin. Hb X has been previously detected in human embryos; we show here that it has the composition Eay2 and is diagnostic of imbalanced chain synthesis or' % thalassemia."We have identified several agents that induce hemoglobin synthesis in K562 cells. Different inducers induced different patterns of embryonic hemoglobin synthesis but never any adult hemoglobin synthesis.One of the limitations to the study of the factors regulating the changes in human hemoglobin production that occur between embryonic, fetal, and adult life (1) has been the lack of a selfsustaining cell line in which human hemoglobin genes are expressed. Recently, Andersson et al. (2,3) reported that the human cell line K562, derived from a patient who had chronic myeloid leukemia in terminal blast cell crisis (4), has certain erythroid characteristics. In a preliminary report (5), we have shown that these cells can be induced to produce embryonic and fetal but not adult hemoglobin. In this paper, we report an analysis ofthe potential ofthe K562 cell line as a model for studying hemoglobin differentiation.Lozzio et al., who established the K562 cell line in culture (4) have questioned the erythroid nature of K562 cells (6). If the pattern of globin synthesis we observed is the consequence of abnormal and unstable gene expression in a leukemic cell line or the result of gene rearrangement in culture, the utility of these cells for the study of the normal control of hemoglobin synthesis would be slight.We found that the cells available to us showed a stable pattern of erythroid differentiation in response to hemin and that embryonic hemoglobins were synthesized but adult (13) globin synthesis was strictly repressed. This is the converse of the situation in normal adult erythroid tissue but closely resembles the state of the normal embryo. Restriction endonuclease analysis of the globin genes has failed to detect any gene deletion or rearrangements, and we thus propose that the presence of embryonic and the absense of adult globin synthesis is the consequence of epigenetic control analogous to that in normal embryonic erythroid cells. Nevertheless, by selection of variant cell lines and the choice of hemoglobin inducer, the varieties of hemoglobin produced c...

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mentioning

confidence: 96%

Embryonic erythroid differentiation in the human leukemic cell line K562.

Rutherford¹,

Clegg²,

Higgs³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

162

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“…14,29 If the clinician is able to obtain blood before the need for red blood cell transfusions, a hemoglobin electrophoresis can be useful in helping to establish the diagnosis, as greater than 50% of JMML patients will demonstrate a reversion to fetal red blood cell characteristics, including (1) increased levels of hemoglobin F, even when corrected for age, (2) low carbonic anhydrase levels and (3) expression of the i antigen. 30 It should be emphasized that elevated fetal hemoglobin levels are not necessary for a diagnosis of JMML, due to the fact that at least one-third of confirmed JMML diagnoses have normal fetal hemoglobin levels. Furthermore, the hemoglobin F level elevations can cover a broad range from as little as a few percent to as much as 70-80%.…”

Section: Jmmlflaboratory Findingsmentioning

confidence: 99%

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

2008

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“…An interesting feature of two-thirds of cases (specifically, those without chromosome 7 abnormality; see below) is the reversal to fetal red cell characteristics, including increased levels of hemoglobin F, expression of the i antigen and low carbonic anhydrase levels. 4 Therefore, hemoglobin electrophoresis may help establish the diagnosis. JMML responds poorly to chemotherapy regardless of its intensity, 5 and presently allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapeutic modality.…”

mentioning

confidence: 99%

How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia

Flotho¹,

Kratz²,

Niemeyer³

2007

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nderived from peripheral blood or bone marrow of JMML patients form excessive numbers of granulocytemacrophage colonies in vitro even when cultured without exogenous cytokines.12 This phenomenon is known as spontaneous proliferation and depends on the presence of leukemic monocytes.13 Second, dose-response experiments demonstrated that JMML myeloid progenitor cells are hypersensitive to GM-CSF.14 It is likely that constitutive low-level secretion of cytokines, primarily GM-CSF, by leukemic monocytes, coupled with the hypersensitivity of granulocyte-macrophage colony-forming units to these stimuli, is sufficient to drive the excessive myeloproliferation. Although not absolutely specific for JMML, GM-CSF hypersensitivity is a key feature of the disease and has become a valuable diagnostic tool. In addition, it pointed the way to major advances in our understanding of the molecular pathogenesis of JMML. Today, gene mutations interfering with downstream components of the GM-CSF signal transduction pathway can be defined in approximately 70% of children with this disorder.The transmission of GM-CSF signals from its receptor to the nucleus occurs mainly through the sequential phosphorylation of a series of intracellular proteins centered around the RAS signal transduction pathway, 15 as reviewed in more detail by Downward.16 Functioning as cellular master switches, RAS proteins bind guanosine triphosphate (RAS-GTP) in their active configuration and guanosine diphosphate (RAS-GDP) when inactive.17 The cellular levels of active RAS-GTP are balanced within tight boundaries by the concurrent action of guanine nucleotide exchange factors (GNEF) and GTPase-activating proteins (GAP).18 Extracellular stimuli, such as GM-CSF binding to its receptor, activate adaptor molecules (e.g., GRB2, SHC, GAB2) which recruit GNEF (e.g., SOS1) to turn on RAS by displacing GDP and allowing GTP to bind (Figure 2). Active RAS forwards the signal to RAF1, PI3K, RALGDS and other effector molecules.19 RAS itself possesses intrinsic GTPase activity which hydrolyses RAS-GTP to RAS-GDP and thus terminates the signal.20 GAP, most notably the NF1 gene product, neurofibromin, dramatically accelerate this process, serving as molecular brakes on the RAS pathway. 19,20 The following paragraphs will briefly describe how the various genetic lesions observed in JMML result in deregulation of RAS signaling. There are three prominent RAS proto-oncogenes in the human genome, termed NRAS, KRAS and HRAS, which were originally identified as orthologs of rat sarcoma virus oncogenes. Point mutations at codons 12, 13 or 61 of NRAS, KRAS or HRAS are commonly encountered in a broad spectrum of human cancers and leukemias. 21 The mutations affecting these residues lead to RAS proteins with reduced capacity for GTP hydrolysis and resistance to GAP, resulting in overstimulation of RAS-dependent target molecules in the nucleus. In JMML, somatic mutations of the NRAS or KRAS (but not HRAS) genes are found in leukemic cells at dia...

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Haemoglobin and red cell enzyme changes in juvenile myeloid leukaemia.

Cited by 104 publications

References 13 publications

Embryonic erythroid differentiation in the human leukemic cell line K562.

Embryonic erythroid differentiation in the human leukemic cell line K562.

Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia

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