Divergent clonal evolution of blastic plasmacytoid dendritic cell neoplasm and chronic myelomonocytic leukemia from a shared TET2-mutated origin

From Springer Nature via Jisc Publications RouterHistory: received 2020-11-25, rev-recd 2021-02-15, accepted 2021-03-11, registration 2021-03-12, pub-electronic 2021-04-08, online 2021-04-08, pub-print 2021-11Publication status: PublishedFunder: Oglesby Charitable TrustFunder: Pickering family donationFunder: Blood Cancer UK Clinician Scientist Fellowship (15030) Oglesby Charitable Trus

Very high frequencies of leukaemia-initiating cells in precursor T-acute lymphoblastic leukaemia may be obscured by cryopreservation

No abstract available

Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1.

Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia

Comparison of the clinical features of male patients with deletion in 2p14-p16.1 that encompasses <i>OTX1</i>.

<p>VUR  =  vesicoureteral reflux; NM  =  not mentioned.</p><p>Comparison of the clinical features of male patients with deletion in 2p14-p16.1 that encompasses <i>OTX1</i>.</p

Analysis of an <i>OTX1</i> deletion in subject 1 with BEEC.

<p>A) NimbleGen aCGH revealed a microdeletion of 66 kb at 2p15 that encompasses only <i>OTX1</i> (blue dots indicate probe position). B) Validation of NimbleGen aCGH results with a custom Agilent aCGH for that microdeletion. Green dots indicate the area of microdeletion. C) <i>OTX1</i>-Taqman-CNV assays validated the microdeletion showing one copy of the gene (red bar) in the subject-1 and 12 other BEEC subjects with normal copy number (blue bars).</p

Schematic of the chromosome 2p regions deleted in our subjects and in those males identified in the literature.

<p>Top panel represents chromosome 2p16.1p14 showing the seven male subjects in our study together with the size of their microdeletions, as well as a brief description of the of GU defects present in each patient. Gray rectangles represent the minimum deletion regions and horizontal black lines extend through gaps in coverage to show the maximum deletion size. The location of <i>OTX1</i> (the only gene commonly deleted in all seven of our subjects) is indicated by a vertical line. Middle and bottom panels show all the male patients described with the 2p15p16.1 and 2p14p15 microdeletion syndromes, respectively, indicating the size of the deletion and their GU defects. Coordinates shown correspond to the hg18 build of the human genome.</p