The MLL at the 66th ASH Annual Meeting & Exposition – A Recap

The progression from clonal hematopoiesis (CH) through myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) is a complex biological process that has been the focus of scientific research for years. The identification of specific mutations and their role in disease progression remains a central and fascinating topic, as highlighted by several of the MLL's contributions this year.

Huber et al. provided insight into the molecular evolution of these diseases. Their study, presented as a poster at ASH, analyzed the presence and co-occurrence of DNMT3A, TET2, and ASXL1 (DTA) mutations in 1,604 cases of clonal cytopenia of undetermined significance (CCUS), MDS, and AML. The results indicate that DTA mutations are more common in CCUS in isolation but occur in more complex patterns in MDS and AML.

Another study presented as a poster by Marcinek et al. focused on the progression from CH to AML. They concluded that in most of the 480 cases studied, AML-defining genetic abnormalities, rather than CH-associated mutations, were the first disease-triggering events. This was particularly true for patients with PML::RARA-positive AML.

Ecker et al. investigated the phenotypic and genetic diversity of AML with NPM1 mutations at diagnosis and during disease progression. Their retrospective analysis of 80 patients showed that co-mutations, especially DNMT3A and IDH2, often represented the dominant clone. The frequency and type of co-mutations, as well as the correlation between MRD levels and methods, varied by immunophenotype.

In another study, Haferlach et al. investigated the development of myeloid neoplasms, focusing on complex karyotypes in MDS. Their analysis of 729 MDS patients with del(5q) suggested two distinct pathways to a complex karyotype: one involving the acquisition of TP53 alterations during disease progression, and another, more common pathway in which clones with primary TP53 mutations later acquire del(5q).

The mutational landscape of SH2B3, a negative regulator of cytokine signaling and cell proliferation, was analyzed by Wossidlo et al. Their study showed that mutated SH2B3 was most common in patients with chronic myelomonocytic leukemia (CMML, 8%), followed by CML (5.6%) and MDS/MPN (5.4%). The high incidence of pathogenic SH2B3 variants and their association with lower risk CMML categories suggest a specific role for SH2B3 in this entity and warrant further investigation.

In her talk, called Secondary Cytogenetic and Molecular Genetic Abnormalities in Newly Diagnosed Multiple Myeloma Patients (Wobst et al.), Dr. rer. nat. Jana Wobst conducted a comprehensive analysis of secondary cytogenetic abnormalities (CA) and mutations. They examined their associations with primary CA in 807 newly diagnosed multiple myeloma (MM) patients and found that high-risk secondary CAs, such as del(1p) and +1q, were significantly associated with primary high-risk markers. Further research is needed to determine whether these primary or secondary markers are the key drivers of poor prognosis.

Walter et al. investigated the genetic characterization of acute lymphoblastic leukemia (ALL), focusing on B-precursor ALL (BCP-ALL) cases with dic(9;20). Their study concluded that dic(9;20) cases do not form a distinct subgroup, but can be classified into existing subtypes such as PAX5 P80R and PAX5alt.

Learn more about MLL research projects on our website. Links to all MLL contributions at this year’s ASH conference can be found here: