ASH 2024 | Myeloid mutations in ALL and their role in identifying those at risk of secondary malignancies

So acute lymphoblastic leukemia is well known for being characterized by multiple genomic subtypes that are driven by fusions, cryptic rearrangements, even specific sequence mutations. However, there are a lot of cooperating genetic lesions that are recurrent and they contribute to pathogenesis. Recently, it has been described in adult cases that myeloid mutations can occur as a consequence of clonal hematopoiesis of indeterminate potential. So these mutations occur within stem cells and they promote a pre-leukemic expansion. And when other alterations occur in lymphoid progenitors, then they can contribute to the development of acute lymphoblastic leukemia. Mostly these mutations involve genes such as IDH2, DNMT3A, RUNX1 and these are often identified in patients with specific subtypes such as BCR-ABL-positive, BCR-ABL-like or KMT2A or in patients with hyperdiploid ALL. Indeed in these latter subtypes mutations of TP53 which are very common in the pediatric setting, they are often a consequence of germline mutations. Conversely, in the adults, they are a consequence of clonal hematopoiesis. And so these mutations are the founder events that predispose the genome to genetic instability and accumulation of other mutations. Of course the presence of these mutations is crucial because it’s not only identifiable in leukemic blasts but it’s also in myeloid or T normal cells. And so the identification of these mutations within non-lymphoid blasts is also an indication of clonal hematopoiesis. The clinical relevance is that this mutation can predispose to secondary malignancies. For example, myeloid malignancies can occur after the acute lymphoblastic leukemia goes to remission if other alterations are acquired.

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