Parthenolide eliminates leukemia-initiating cell populations and improves survival in xenografts of childhood acute lymphoblastic leukemia

Key Points First report demonstrating in vivo elimination of multiple LIC populations from childhood ALL cases using animal models. In vivo models of leukemia are essential for drug evaluation studies.</jats:p

Targeting pediatric leukemia propagating cells using anti-CD200 antibody therapy.

Treating refractory pediatric acute lymphoblastic leukemia (ALL) remains a challenge despite impressive remission rates (>90%) achieved in the last decade. The use of innovative immunotherapeutic approaches such as anti-CD19 chimeric antigen receptor T cells does not ensure durable remissions, because leukemia-propagating cells (LPCs) that lack expression of CD19 can cause relapse, which signifies the need to identify new markers of ALL. Here we investigated expression of CD58, CD97, and CD200, which were previously shown to be overexpressed in B-cell precursor ALL (BCP-ALL) in CD34(+)/CD19(+), CD34(+)/CD19(–), CD34(–)/CD19(+), and CD34(–)/CD19(–) LPCs, to assess their potential as therapeutic targets. Whole-genome microarray and flow cytometric analyses showed significant overexpression of these molecules compared with normal controls. CD58 and CD97 were mainly co-expressed with CD19 and were not a prerequisite for leukemia engraftment in immune deficient mice. In contrast, expression of CD200 was essential for engraftment and serial transplantation of cells in measurable residual disease (MRD) low-risk patients. Moreover, these CD200(+) LPCs could be targeted by using the monoclonal antibody TTI-CD200 in vitro and in vivo. Treating mice with established disease significantly reduced disease burden and extended survival. These findings demonstrate that CD200 could be an attractive target for treating low-risk ALL, with minimal off-tumor effects that beset current immunotherapeutic approaches

Rationale and design of the HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) Trial : a protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Peer reviewedPublisher PD

Molecular characterisation and clinical outcome of B-cell precursor acute lymphoblastic leukaemia with IG-MYC rearrangement

Rarely, immunophenotypically immature B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) carries an immunoglobulin-MYC rearrangement (IG-MYC-r). This can result in diagnostic confusion with Burkitt lymphoma/leukaemia and use of unproven individualised treatment schedules. Here we contrast the molecular characteristics of these conditions and investigate historic clinical outcome data. We identified 90 cases registered on a national BCP-ALL clinical trial/registry. Where present, diagnostic material underwent cytogenetic, exome, methylome and transcriptome analysis. Outcome was analysed to define 3-year event free survival (EFS) and overall survival (OS). IG-MYC-r was identified in diverse cytogenetic backgrounds, co-existing with either: established BCP-ALL specific abnormalities (high hyperdiploidy n=3, KMT2A-rearrangement n=6, iAMP21 n=1, BCR-ABL n=1); BCL2/BCL6-rearrangements (n=15); or, most commonly, as the only defining feature (n=64). Within this final group, precursor-like V(D)J breakpoints predominated (8/9) and KRAS mutations were common (5/11). DNA methylation identified a cluster of V(D)J rearranged cases, clearly distinct from Burkitt leukaemia/lymphoma. Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols

Expression of CD99 in T-ALL and normal hemopoietic cells.

<p>(A) Expression of CD99 antigen was assessed by flow cytometry in BM samples from 9 T-ALL cases and BM MNC, CD34⁺/CD38^- HSC and CD3⁺ T cells from 5–9 healthy donors. Lines represent median values, ** <i>P</i>≤0.007, **** <i>P</i><0.0001. (B) Expression of CD99 in sorted LPC subpopulations from this T-ALL cohort. Lines represent median values, * <i>P</i> = 0.02, ** <i>P</i>≤0.009. (C) Stacked bar chart showing expression of CD99 in CD34/CD7 LPC subpopulations in individual cases. (D) Gene expression in BM samples from 5 T-ALL cases (pts 2, 4, 7, 8, 9) and from 5 healthy donors were analyzed using Agilent Whole Genome Oligo microarrays. Data shows side by side comparisons of median centered normalized log2 signal intensities. Boxes represent the range of expression and the horizontal lines represent the median.</p