Covert preleukemia driven by MLL gene fusion

Abstract

Acute leukemia is considered to be a two-or multiple-step process. Although there is a considerable knowledge regarding the character of the ''first hit,'' the nature of the ''second hit'' remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential ''second hit'' precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.

Acute lymphoblastic leukemia with aleukemic prodrome: preleukemic dynamics and possible mechanisms of immunosurveillance

“…The (pre)leukaemic clonal dynamics described here are consistent with our observations in secondary leukemias, 5,6 and the fluctuation in the percentage of ETV6-RUNX1-positive cells detected by fluorescence in situ hybridization described in another ALL patient with a preleukemic phase. 7 This suggests that some immunological mechanisms might be capable of temporary surveillance over the pre-malignant clones, at least in some leukemia subtypes.…”

Cellular Reprogramming Allows Generation of Autologous Hematopoietic Progenitors From AML Patients That Are Devoid of Patient-Specific Genomic Aberrations

“…It has been postulated that preleukemic mutations may predispose cells to genomic instability and increase their susceptibility to acquiring disease-specific secondary mutations 57 , 58 due to enhanced cell survival properties 59 . Recent utilization of next-generation sequencing technologies has enabled identification of preleukemic mutations in HSCs 60 , 61 , and forms the basis for future delineation of early genetic events that contribute to leukemogenesis.…”

CircRNAs in hematopoiesis and hematological malignancies

“…65 Foxo3 is a forkhead box O transcription factor and may behave as a tumour suppressor protein that limits cell proliferation and induces apoptosis and is frequently altered in cancer, shown to be deleted in lymphomas (diffuse large B-cell lymphoma), and translocated with MLL in leukemia. 66 In healthy cells high circ-Foxo3 expression was found to be associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation, whereas ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to cell cycle proteins cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase inhibitor 1 (or p21).…”