SummaryMLL-AF4+ infant B cell acute lymphoblastic leukemia is characterized by an early onset and dismal survival. It initiates before birth, and very little is known about the early stages of the disease’s development. Using a conditional Mll-AF4-expressing mouse model in which fusion expression is targeted to the earliest definitive hematopoietic cells generated in the mouse embryo, we demonstrate that Mll-AF4 imparts enhanced B lymphoid potential and increases repopulation and self-renewal capacity during a putative pre-leukemic state. This occurs between embryonic days 12 and 14 and manifests itself most strongly in the lymphoid-primed multipotent progenitor population, thus pointing to a window of opportunity and a potential cell of origin. However, this state alone is insufficient to generate disease, with the mice succumbing to B cell lymphomas only after a long latency. Future analysis of the molecular details of this pre-leukemic state will shed light on additional events required for progression to acute leukemia.
Despite the frequent use and radiation exposure of computed tomography (CT) scans, there is little information on patterns of CT use and their utility in the management of pediatric patients with fever and neutropenia (FN). We examined the contribution of either the commonly employed pan-CT (multiple anatomical locations) or targeted CT (single location) scanning to identify possible infectious etiologies in this challenging clinical scenario. Procedure Pediatric patients with an underlying malignancy admitted for fever (temperature ≥ 38.3 °C) and an absolute neutrophil count <500 cells/μL from 2003-2009 were included. Risk factors associated with utilization, results, and effects on clinical management of CT scans were identified. Results Charts for 635 admissions for FN from 263 patients were reviewed. Overall, 139 (22%) admissions (93 individuals) had at least one scan. Of 188 scans, 103 (55%) were pan-scans. Changes in management were most strongly associated with the identification of evidence consistent with infection (OR = 12.64, 95% CI: 5.05-31.60, P < 0.001). Seventy-eight (41%) of all CT scans led to a change in clinical management, most commonly relating to use of antibiotic (N = 41, 53%) or antifungal/antiviral medications (N = 33, 42%). The odds of a change in clinical management did not differ for those receiving a pan-scan compared to those receiving a targeted scan (OR = 1.23; 95% CI, 0.61-2.46; P = 0.57). Conclusions When CT is clinically indicated, it is important for clinicians to strongly consider utilizing a targeted scan to reduce radiation exposure to patients as well as to decrease costs without compromising care.
Neil Barrett discusses the unusual haematological implications of accidental transfusion from a close relative in the high profile case of the She-Hulk, barriers to future research, and the real heroes in this
Acute leukemia is the most common malignancy of childhood. The pattern of incidence of childhood leukemia reveals how age at diagnosis is associated with particular molecular subtypes, responsiveness to treatment and outcome. Translocations involving the Mixed Lineage Leukemia gene (MLL) in particular are associated with the diagnosis of acute leukemia in infancy. As with other forms of childhood leukemia, evidence from retrospective cohort analysis of neonatal blood spots suggests that MLL translocations are present at birth in many of these cases, indicating that the initial steps towards leukemia development occurred in utero (Greaves Early Human Development 2005). Concurrently there has been increasing recognition of the differences between the foetal and adult hematopoietic cells and supportive niches. These differences might have profound effects on a cell’s ability to undergo malignant transformation and its subsequent properties. Unlike mouse models of myeloid leukemia associated with MLL fusions, previous attempts to mouse model acute lymphoid leukemia of infancy associated with the MLL-AF4 fusion gene have had mixed results, with unsatisfactory disease latencies and phenotypes (Stam Cell Research 2012). However, many of these models have introduced the translocation only within the adult hematopoietic system – discounting the possible effect of this mutation in utero. The aim of this study was to examine the effect of MLL-AF4 within the context of the varied hematopoietic sites of the developing embryo, and how the induction of MLL-AF4 within these niches might influence subsequent disease development. For this, we utilised the Cre inducible Mll-AF4 “invertor mouse” that has previously been described (Metzler et al Oncogene 2006). As embryonic stem cell work suggests MLL-AF4 may alter the emergence of Hematopoietic Stem Cells (HSCs) from the hemogenic precursors (Bueno Cell Research 2012), we crossed the invertor mice with Ve-cadherin-Cre and Vav-Cre murine lines to induce Mll-AF4 expression in (pre)HSCs before and after this critical time point. HSC and progenitor populations at several established hematopoietic sites through ontogeny were assessed by flow cytometry and functional assays, including in vitro methylcellulose based colony forming assays and in vivo transplantation assays. Mice were also bred to adulthood and observed for the development of disease. Despite no statistically significant changes in HSC and progenitor populations within in utero HSC niches, functional assays reveal marked differences in both myeloid and lymphoid colony forming assays with a particularly strong effect seen in lymphoid assays; however, despite evidence of a limited increase in serial repeatability, these cells did not appear to be fully transformed and could not be re-plated successfully beyond the third round. In vivo transplantation assays also showed enhanced multi-lineage engraftment by foetal liver cells carrying the Mll-AF4 fusion gene. Adult mice developed both B and T cell malignancies with long latencies and median survival of 437 day to 551 days for Mll-AF4xVeCadherin-Cre and Mll-AF4xVav-Cre lines, respectively. We have thus shown for the first time that the induction of Mll-AF4 has an effect on the myeloid and lymphoid output of foetal derived HSCs. Although this effect appears to fall short of full transformation, the development of lymphoid malignancies in adult mice suggests that such cells have pre-malignant potential. We continue to explore the mechanism of these early pre-malignant effects and aim to explore how additional factors may unlock the true malignant potential of MLL-AF4 in murine model systems. Disclosures No relevant conflicts of interest to declare.
Infants and children with MLL-AF4+ leukemia have an urgent need for more efficient and less aggressive therapy. In this study, we studied three microRNAs that are downregulated in MLL-AF4+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of MLL-AF4+ leukemic blasts and the maintenance of MLL-AF4+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in MLL-AF4+ BCP-ALL: CA5B, PPP3CA and PPP2R5C. Using CRISPR-Cas9 and specific inhibitors, we confirmed that CA5B, PPP3CA and PPP2R5C downregulation/inhibition severely compromised the proliferation and survival of MLL-AF4+ leukemic blasts. Importantly, CA5B, PPP3CA and PP2A inhibition by acetazolamide, tacrolimus and LB-100, respectively, showed high toxicity towards MLL-AF4+ leukemic blasts and reduced leukemia burden in vivo. This study highlights how the unique microRNA expression signature of patients with MLL-AF4+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing.
Advances in genomic diagnostics hold promise for improved care of rare hematologic diseases. Here we describe a novel targeted therapeutic approach for Ghosal hematodiaphyseal dysplasia, an autosomal recessive disease characterized by severe normocytic anemia and bone abnormalities due to loss-of-function mutations in Thromboxane A Synthase 1 (TBXAS1). TBXAS1 metabolizes prostaglandin (PG)H2, the cyclooxygenase (COX) product of arachidonic acid, into thromboxane A2. Loss-of-function in TBXAS results in an increase in PGH2 availability for other PG synthases. Current treatment for Ghosal syndrome consists of corticosteroids. We hypothesized that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit COX-1 and COX-2, could ameliorate the effects of TBXAS1 loss and improve hematologic function by reducing prostaglandin formation. We treated two patients with Ghosal syndrome, one adult and one pediatric, with standard doses of NSAIDs (aspirin or ibuprofen). Both patients had rapid improvement of hematologic parameters and inflammatory markers without adverse events. Mass spectrometry analysis demonstrated that urinary PG metabolites were increased along with proinflammatory lipoxygenase (LOX) products 5-Hydroxyeicosatetraenoic acid and leukotriene E4. Our data show that NSAIDs at standard doses surprisingly reduced both COX and LOX products, leading to the resolution of cytopenias, and should be considered for first-line treatment for Ghosal syndrome.
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