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Author |
Gawad, C.; Pepin, F.; Carlton, V.; Klinger, M.; Logan, A.C.; Miklos, D.B.; Faham, M.; Dahl, G.; Lacayo, N. |
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Title |
Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia |
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Journal Article |
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Year |
2012 |
Publication |
Blood |
Abbreviated Journal |
Blood |
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Abstract |
The ability to distinguish clonal B-cell populations based on the sequence of their rearranged immunoglobulin heavy chain (IgH) locus is an important tool for diagnosing B-cell neoplasms and monitoring treatment response. Leukemic precursor-B-cells may continue to undergo recombination of the IgH gene after malignant transformation; however, the magnitude of evolution at the IgH locus is currently unknown. We used next-generation sequencing to characterize the repertoire of IgH sequences in diagnostic samples of 51 children with B precursor acute lymphoblastic leukemia (B-ALL). We identified clonal IgH rearrangements in 43 of 51 (84%) cases and found that the number of evolved IgH sequences per patient ranged dramatically from 0 to 4,024. We demonstrate that the evolved IgH sequences are not due to amplification artifacts and are unique to leukemic precursor-B-cells. In addition, the evolution often follows an allelic exclusion pattern, where only one of two rearranged IgH loci exhibit ongoing recombination. Thus, precursor-B-cell leukemias maintain evolution at the IgH locus at levels that were previously under-appreciated. This finding sheds light on the mechanisms associated with leukemic clonal evolution and may fundamentally change approaches for monitoring minimal residual disease burden. |
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Address |
Stanford University School of Medicine, Department of Pediatrics, Division of Hematology-Oncology-Stem Cell Transplantation and Cancer Biology, Stanford, CA, United States |
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0006-4971 |
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Notes |
PMID:22932801 |
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CBM.UAM @ ccobaleda @ |
Serial |
227 |
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Author |
Capstick, M.; Schar, P.; Schuermann, D.; Romann, A.; Kuster, N. |
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Title |
ELF exposure system for live cell imaging |
Type |
Journal Article |
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Year |
2012 |
Publication |
Bioelectromagnetics |
Abbreviated Journal |
Bioelectromagnetics |
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Abstract |
A programmable system has been developed for the study of both transient and persistent effects of extremely low frequency (ELF) magnetic field exposure of cell cultures. This high-precision exposure system enables experimental blinding and fully characterized exposure while simultaneously allowing live cell imaging. It is based on a live imaging cell around which two asymmetrical coils are wound in good thermal contact to a temperature-controlled water jacket, and is mounted on a microscope stage insert. The applied B-field uniformity of the active volume is better than 1.2% with an overall exposure uncertainty of less than 4.3% with very low transient field levels. The computer-controlled apparatus allows signal waveforms that are sinusoidal or composed of several harmonics, blind protocols, and monitoring of exposure and environmental conditions. B-fields up to 4 mT root mean square amplitude are possible with minimal temperature variation and no recognizable temperature differences between exposure and sham states. Sources of artifacts have been identified and quantified. There are no visible vibrations observable even at the highest magnifications and exposure levels. Bioelectromagnetics. (c) 2012 Wiley Periodicals, Inc. |
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Address |
IT'IS Foundation, Zurich, Switzerland. capstick@itis.ethz.ch |
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English |
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0197-8462 |
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PMID:23125057 |
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CBM.UAM @ ccobaleda @ |
Serial |
228 |
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Rehe, K.; Wilson, K.; Bomken, S.; Williamson, D.; Irving, J.; den Boer, M.L.; Stanulla, M.; Schrappe, M.; Hall, A.G.; Heidenreich, O.; Vormoor, J. |
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Title |
Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations |
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Journal Article |
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Year |
2012 |
Publication |
EMBO Molecular Medicine |
Abbreviated Journal |
EMBO Mol Med |
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n/a-n/a |
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Abstract |
Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic
leukaemia than in many malignancies that follow a hierarchical cancer
stem cell model. It is unclear whether this characteristic can be more universally
applied to patients from non-‘high-risk’ sub-groups and across a broad range of
cellular immunophenotypes. Here, we demonstrate in a wide range of primary
patient samples and patient samples previously passaged through mice that
leukaemia-propagating cells are found in all populations defined by high or low
expression of the lymphoid differentiation markers CD10, CD20 or CD34. The
frequency of leukaemia-propagating cells and their engraftment kinetics do
not differ between these populations. Transcriptomic analysis of CD34high and
CD34low blasts establishes their difference and their similarity to comparable
normal progenitors at different stages of B-cell development. However, consistent
with the functional similarity of these populations, expression signatures
characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to
distinguish between the different populations. Together, these findings suggest
that there is no stem cell hierarchy in acute B lymphoblastic leukaemia. |
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ISSN |
1757-4676 |
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CBM.UAM @ ccobaleda @ |
Serial |
233 |
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Author |
Mullighan, C.G. |
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Title |
The molecular genetic makeup of acute lymphoblastic leukemia |
Type |
Journal Article |
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Year |
2012 |
Publication |
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program |
Abbreviated Journal |
Hematology Am Soc Hematol Educ Program |
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Volume |
2012 |
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Pages |
389-396 |
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Abstract |
Genomic profiling has transformed our understanding of the genetic basis of acute lymphoblastic leukemia (ALL). Recent years have seen a shift from microarray analysis and candidate gene sequencing to next-generation sequencing. Together, these approaches have shown that many ALL subtypes are characterized by constellations of structural rearrangements, submicroscopic DNA copy number alterations, and sequence mutations, several of which have clear implications for risk stratification and targeted therapeutic intervention. Mutations in genes regulating lymphoid development are a hallmark of ALL, and alterations of the lymphoid transcription factor gene IKZF1 (IKAROS) are associated with a high risk of treatment failure in B-ALL. Approximately 20% of B-ALL cases harbor genetic alterations that activate kinase signaling that may be amenable to treatment with tyrosine kinase inhibitors, including rearrangements of the cytokine receptor gene CRLF2; rearrangements of ABL1, JAK2, and PDGFRB; and mutations of JAK1 and JAK2. Whole-genome sequencing has also identified novel targets of mutation in aggressive T-lineage ALL, including hematopoietic regulators (ETV6 and RUNX1), tyrosine kinases, and epigenetic regulators. Challenges for the future are to comprehensively identify and experimentally validate all genetic alterations driving leukemogenesis and treatment failure in childhood and adult ALL and to implement genomic profiling into the clinical setting to guide risk stratification and targeted therapy. |
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Address |
1Hematological Malignancies Program, and |
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English |
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Edition |
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ISSN |
1520-4383 |
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Notes |
PMID:23233609 |
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no |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
234 |
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Author |
Wakeford, R. |
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Title |
The risk of childhood leukaemia following exposure to ionising radiation—a review |
Type |
Journal Article |
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Year |
2013 |
Publication |
Journal of Radiological Protection |
Abbreviated Journal |
J. Radiol. Prot. |
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Volume |
33 |
Issue |
1 |
Pages |
1-25 |
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Abstract |
Since the early years of follow-up of the Japanese atomic-bomb survivors, it has been apparent that childhood leukaemia has a particular sensitivity to induction by ionising radiation, the excess relative risk (ERR) being expressed as a temporal wave with time since exposure. This pattern has been generally confirmed by studies of children treated with radiotherapy. Case-control studies of childhood leukaemia and antenatal exposure to diagnostic x-rays, a recent large cohort study of leukaemia following CT examinations of young people, and a recent large case-control study of natural background γ-radiation and childhood leukaemia have found evidence of raised risks following low-level exposure. These findings indicate that an ERR/Sv for childhood leukaemia of ~50, which may be derived from risk models based upon the Japanese atomic-bomb survivors, is broadly applicable to low dose or low dose-rate exposure circumstances. |
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ISSN |
0952-4746 |
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no |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
235 |
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