Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.

Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-riskJAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance inJAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model ofATF7IP-JAK2with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within theJAK2ATP/rux binding site, including aJAK2p.G993A mutation. Using in vitro models ofJAK2r B-ALL,JAK2p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate thatJAK2p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.

Chromosomal rearrangements involving the KMT2A gene occur frequently in acute lymphoblastic leukaemia (ALL). KMT2A-rearranged ALL (KMT2Ar ALL) has poor long-term survival rates and is the most common ALL subtype in infants less than 1 year of age. KMT2Ar ALL frequently occurs with additional chromosomal abnormalities including disruption of the IKZF1 gene, usually by exon deletion. Typically, KMT2Ar ALL in infants is accompanied by a limited number of cooperative le-sions. Here we report a case of aggressive infant KMT2Ar ALL harbouring additional rare IKZF1 gene fusions. Comprehensive genomic and transcriptomic analyses were performed on sequential samples. This report highlights the genomic complexity of this particular disease and describes the novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1.

Multiple myeloma (MM) is a malignancy characterised by the uncontrolled proliferation of clonal plasma cells, primarily within the bone marrow, and is still considered incurable. A significant proportion of patients relapse with drug-refractory disease, necessitating the development of novel therapeutic approaches. Ferroptosis is a recently-characterised form of non-apoptotic programmed cell death, linked to phospholipid peroxidation, that represents a promising approach for the treatment of MM and other cancers, that are refractory to more conventional apoptosis-inducing regimens. A better understanding of the relationship between cellular lipid composition and ferroptosis sensitivity is key to harnessing this form of programmed cell death as a therapeutic approach. In addition to the cellular proportions of phospholipids containing poly- and monounsaturated fatty acids, studies to date indicate that cholesterol levels impact not only the onset and progression of haematological malignancies but also the sensitivity of a variety of different cancers to ferroptosis. Therefore, manipulating the uptake and metabolism of lipids, including glycerophospholipids and cholesterol, may be an effective means of sensitising MM cells to ferroptosis. Findings from the limited number of studies concerning ferroptosis in MM and compelling evidence from other malignancies, provide a strong rationale for further investigation of ferroptosis as a novel therapeutic approach for MM.