Charles Mullighan, MBBS (Hons), MSc, MD, from St. Jude Children’s Research Hospital, Memphis, TN, introduces new subtypes of acute lymphoblastic leukemia (ALL) at the International Symposium on Acute Leukemias (ISAL) 2017 in Munich, Germany. He describes how in the past, one chromosomal alteration was found in each subtype, and was detected by conventional methods such as cytogenetic karyotyping or fluorescence in situ hybridization (FISH). However, we now know that these approaches fail to detect some subtypes which may have complex alterations not visible in conventional karyotypes, or where multiple different rearrangements are found within one ALL group. Diagnostics in these cases are more complex, and may require other approaches such as RNA sequencing or whole genome sequencing. Dr Mullighan outlines several subtypes which have recently generated interest. Ph-like ALL is very common, and found in around 25% of all ALL cases. It is typically associated with high-risk features and poor outcomes. Dr Mullighan explains that Ph-like ALL is genetically perhaps the most diverse of any leukemia subtype, with around 50 different chromosomal rearrangements, structural changes and point mutations activating a variety of cytokine receptor and kinase signaling pathways. These are clinically interesting as in vitro studies have shown these mutations to be disease driving lesions, and they can often be treated with tyrosine kinase inhibitors (TKI). Some patients with refractory disease respond well to TKIs on their own, and prospective studies are underway to evaluate the efficacy of these agents as a frontline therapy in combination with chemotherapy. In MEF2D-rearranged ALL, the transcription factor myocyte-specific enhancer factor 2D is fused to a number of partners, most commonly the Wnt-pathway mediator BCL9, leading to the dysregulation of pathways including the histone deacetylase HDAC9. This indicates a potential vulnerability of this ALL subtype which may be treatable with histone deacetylase inhibitors. Similarly, in ZNF384-rearranged leukemia, which is found in some B-ALL cases, but also highly enriched in B-myeloid mixed phenotype ALL, gene fusion to a number of partners drives the proliferation and expansion of immature, lineage-ambiguous progenitors, and there may be potential therapeutic vulnerability in this case. DUX-4-rearranged ALL is typically associated with good outcomes, and the distinct gene expression profile is often accompanied by a second genetic deletion of the transcription factor ERG resulting in a sequential mechanism of deregulation. This is clinically important not because a more aggressive therapy but a less aggressive therapy may be needed, and both alterations are not detected by cytogenetic karyotyping, so diagnosis and risk stratification require a different strategy. Dr Mullighan concludes that the field of acute lymphoblastic leukemia is rapidly moving towards a next-generation sequencing (NGS) approach.