@article{193bdd261d2e45a1a2feb359b11988b1,
title = "Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia",
abstract = "Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution.",
keywords = "Aplastic anemia, Clonal evolution, Single nucleotide polymorphism array",
author = "Marisol Betensky and Daria Babushok and Roth, {Jacquelyn J.} and Mason, {Philip J.} and Biegel, {Jaclyn A.} and Busse, {Tracy M.} and Yimei Li and Curt Lind and Anna Papazoglou and Dimitri Monos and Gregory Podsakoff and Monica Bessler and Olson, {Timothy S.}",
note = "Funding Information: We thank all patients and their families, as well as their referring physicians for participation in our studies. We are also grateful to Joshua Cockroft, Shanna Cross, Helge Hartung, Michele Paessler, Stella Chou, Beverly Paul, Nieves Perdigones, Peter Nicholas, Jian-meng Fan and members of the Mason and Bessler laboratories for general support of these projects, care provided for our patients, and many helpful discussions. This work was supported by NHLBI 5T32HL007150-38 to M. Betensky, NIH/NCATS Grant UL1TR000003 to the University of Pennsylvania and Children's Hospital of Philadelphia ITMAT/CTRC and T.O, and NIH/NHLBI grants K08 HL122306 to T.O., NIGMS T32-GM008638 to J.R., K12 HL087064 to M. Bessler and T.O., NHLBI/NIH K12 HL097064 and AA & MDS International Foundation Research Grant to D.B., NIH/NCI 5R01-CA105312-1 , NIH/NIDDK R24DK103001 and the Buck Family Endowed Chair in Hematology to M. Bessler. Funding Information: We thank all patients and their families, as well as their referring physicians for participation in our studies. We are also grateful to Joshua Cockroft, Shanna Cross, Helge Hartung, Michele Paessler, Stella Chou, Beverly Paul, Nieves Perdigones, Peter Nicholas, Jian-meng Fan and members of the Mason and Bessler laboratories for general support of these projects, care provided for our patients, and many helpful discussions. This work was supported by NHLBI 5T32HL007150-38 to M. Betensky, NIH/NCATS Grant UL1TR000003 to the University of Pennsylvania and Children''s Hospital of Philadelphia ITMAT/CTRC and T.O, and NIH/NHLBI grants K08 HL122306 to T.O., NIGMS T32-GM008638 to J.R., K12 HL087064 to M. Bessler and T.O., NHLBI/NIH K12 HL097064 and AA & MDS International Foundation Research Grant to D.B., NIH/NCI 5R01-CA105312-1, NIH/NIDDK R24DK103001 and the Buck Family Endowed Chair in Hematology to M. Bessler. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",
year = "2016",
month = jan,
day = "1",
doi = "10.1016/j.cancergen.2015.10.002",
language = "English (US)",
volume = "209",
pages = "1--10",
journal = "Cancer genetics",
issn = "2210-7762",
publisher = "Elsevier BV",
number = "1-2",
}