Abstract Treatment and understanding of BCR::ABL1-positive leukaemias is a precision medicine success story. Our appreciation of the BCR::ABL1 gene and resulting BCR::ABL1 oncoprotein in chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive (Ph+) acute leukaemias, has led to treatment advances associated with exceptional improvements in patient outcomes with normal life expectancy for many patients with chronic phase (CP-)CML. However, despite these major therapeutic advances, the management of Ph+ leukaemias remains complex, with development of specific resistance mutations on treatment, as well as the need for lifelong therapy in most patients due to the persistence of CML stem cells despite prolonged tyrosine kinase inhibitors (TKIs) treatment. BCR::ABL1-specific TKIs are associated with chronic toxicities affecting quality-of-life in many patients but can also result in more serious pulmonary and cardiovascular complications. Dose optimisation is increasingly being used to manage side effects and maintain molecular response in CML patients. Here, we review the development of BCR::ABL1-specific TKIs from the discovery of imatinib in 1996 to the more recent second- and third-generation TKIs and emerging specifically targeting the ABL myristoyl pocket (STAMP) inhibitors. We will also evaluate the current evidence for treatment of BCR::ABL1-positive leukaemias, including TKI discontinuation in optimally responding CP-CML patients.
Silicone lymphadenopathy occurs following migration of silicone particles through the lymphatic system to regional nodes and more distal extranodal sites as a consequence of implant rupture or “gel bleed”. This silicone migration and tissue deposition with granulomatous reaction may cause systemic symptoms which can mimic lymphoma – fatigue, fever, and sweats. It is an important condition to be aware of and to consider in the context of bone marrow granulomatosis. The authors declare no conflicts of interest.
The introduction of tyrosine kinase inhibitors in chronic myeloid leukaemia (CML) has revolutionised disease outcome. However, despite this, progression to blast phase disease is high in those that do not achieve complete cytogenetic and major molecular response on standard therapy. As well as BCR-ABL-dependent mechanisms, disease persistence has been shown to play a key role. Disease persistence suggests that, despite a targeted therapeutic approach, BCR-ABL-independent mechanisms are being exploited to sustain the survival of a small population of cells termed leukaemic stem cells (LSCs). Increasing evidence highlights the importance of self-renewal and survival pathways in this process. This review will focus on the role of stem-cell restricted self-renewal pathways, namely Hedgehog, Notch, and Bone Morphogenic Pathway (BMP). Wingless-Int/β-Catenin (Wnt/β-Catenin) signalling will be discussed within a further review in this series in view of its regulatory role in GSK3β. Further to this, we will highlight the role of key transcriptional regulators, namely p53 and c- MYC, in targeting wider deregulated networks. Keywords: Self-renewal, signalling, CML, leukaemic stem cells.
We agree that it is important to understand whether mutations are responsible for the initiation of AML or cooperate with initiating mutations to cause disease progression or relapse.1,2 Whereas initiating mutations may be more likely to appear in founding clones, cooperating mutations might appear either in founding clones or subclones derived from founding clones. In our study, it was not possible to define the clonal architecture for all samples, both because AML genomes harbor a comparatively small number of mutations and because for 150 of 200 samples, only exome sequencing was performed. Nevertheless, we have used the data in Table S6 (available with the full text of our article at NEJM.org) to identify variants in significantly mutated genes that can be assigned with high confidence to either a founding clone or a subclone.
Mutations in some genes appear almost exclusively in founding clones, which suggests that they are disease initiators. These genes include RUNX1 (9 of 9 mutations in founding clones), NPM1 (3 of 3), U2AF1 (5 of 5), DNMT3A (38 of 40), IDH2 (13 of 14), IDH1 (15 of 17), and KIT(5 of 6). In contrast, mutations in NRAS (1 of 12 in founding clones), TET2 (13 of 18), KRAS(4 of 6), CEBPA (3 of 5), WT1 (3 of 6), PTPN11 (4 of 8), and FLT3 (6 of 13), are often found in subclones, suggesting that they are often cooperating mutations. Many additional genomes will need to be tested to make these tentative assignments more definitive.
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