Abstract
Infants with MLL-rearranged infant acute lymphoblastic leukemia (MLL-r iALL) undergo intense therapy to counter a highly aggressive malignancy with survival rates of only 30–40%. The majority of patients initially show therapy response, but in two-thirds of cases the leukemia returns, typically during treatment. The glucocorticoid drug prednisone is established as a major player in the treatment of leukemia and the in vivo response to prednisone monotreatment is currently the best indicator of risk for MLL-r iALL. We used two different single-cell RNA sequencing technologies to analyze the expression of a prednisone-dependent signature, derived from an independent study, in diagnostic bone marrow and peripheral blood biopsies. This allowed us to classify individual leukemic cells as either resistant or sensitive to treatment and show that quantification of these two groups can be used to better predict the occurrence of future relapse in individual patients. This work also sheds light on the nature of the therapy-resistant subpopulation of relapse-initiating cells. Leukemic cells associated with high relapse risk are characterized by basal activation of glucocorticoid response, smaller size, and a quiescent gene expression program with cell stemness properties. These results improve current risk stratification and elucidate leukemic therapy-resistant subpopulations at diagnosis.
Highlights
Acute lymphoblastic leukemia (ALL) in infants is frequently driven by chromosomal translocations of the mixed lineage leukemia (MLL or KMT2A) gene, which occur in ~80% of the cases
Clustering of leukemic cells according to individual patients To identify subpopulations of cells potentially associated with relapse, we analyzed leukemic cells derived from Bone marrow (BM) biopsies taken at diagnosis
These samples were obtained from seven MLLr iALL patients covering the two most recurrent MLL translocations, t(4;11) and t(11;19), giving rise to the MLL fusion genes MLL-AF4 and MLL-ENL, respectively [1,2,3, 21]
Summary
Acute lymphoblastic leukemia (ALL) in infants (i.e., children < 1 year of age) is frequently driven by chromosomal translocations of the mixed lineage leukemia (MLL or KMT2A) gene, which occur in ~80% of the cases. MLL-rearranged infant ALL (MLL-r iALL) represents a rare but highly aggressive type of childhood leukemia that is notoriously characterized by chemotherapy resistance and high relapse rates, leading to a very poor prognosis. Regardless of the type of MLL translocation, eventfree survival (EFS) rates for MLL-r iALL patients remain at 30–40% when treated according to the international collaborative INTERFANT treatment protocol [2, 3], whereas cases without MLL translocations fare significantly better at 75–80%. In two-thirds of the cases, the leukemia reemerges, typically within the first year from diagnosis and while still on treatment, giving rise to an even more chemotherapy-resistant form
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