MLL–AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny

Abstract

The MLL-AF9 fusion gene is associated with aggressive leukemias of both the myeloid and lymphoid lineage in infants, whereas in adults, this translocation is mainly associated with acute myeloid leukemia. These observations suggest that differences exist between fetal and adult tissues in terms of the 'cell of origin' from which the leukemia develops. Here we show that depending on extrinsic cues, human neonatal CD34(+) cells are readily immortalized along either the myeloid or lymphoid lineage upon MLL-AF9 expression and give rise to mainly lymphoid leukemia in immunocompromised mice. In contrast, immortalization of adult bone marrow CD34(+) cells is more difficult to achieve and is myeloid-biased, even when MLL-AF9 is expressed in purified hematopoietic stem cells (HSCs). Transcriptome analysis identified enrichment of HSC but not progenitor gene signatures in MLL-AF9-expressing cells. Although not observed in adult cells, neonatal cells expressing MLL-AF9 were enriched for gene signatures associated with poor prognosis, resistance to chemotherapeutic agents and MYC signaling. These results indicate that neonatal cells are inherently more prone to MLL-AF9-mediated immortalization than adult cells and suggest that intrinsic properties of the cell of origin, in addition to extrinsic cues, dictate lineage of the immortalized cell.

Insights into cell ontogeny, age, and acute myeloid leukemia

“…In the majority of cases acute lymphoblastic leukaemia developed, but one leukaemia shows mixed myeloid and lymphoid lineage. Transformed CB cells also retained a gene expression signature similar to normal neonatal HSCs [55]. While CB is not an exact surrogate for paediatric BM, this study provides and supports the conceptual basis that AML arising in a young and old cell may be very different.…”

Context matters in MLL-AF9–driven leukemias

“…In the MLL-AF9 knock-in mouse model, FL HSPCs exhibit increased latency and induce leukemias expressing both myeloid and lymphoid markers. 5 In contrast, 6 Although the lineage differences in leukemias from FL and CB HSPCs vs adult HSPCs are thought to reflect cell-of-origin differences between MLL-AF9 1 leukemia in infants and adults, 7 it is not clear whether Id1 participates in determining these lineage differences because the MLL-AF9 retroviral model used in these studies gives rise exclusively to AML. Nonetheless, consistent with the predictions made by these mouse experiments regarding the importance of Id1 expression in infant vs adult-type leukemia, MLL-AF9 1 leukemias from patients age of #3 years express higher levels of Id1 mRNA than patients .3 years of age.…”

“…JAKV617F is an acquired mutation that occurs within the human population, producing a constitutively active Jak2 that drives the formation of myeloproliferative neoplasms (MPNs). [5][6][7][8][9] The JAKV617F mouse model used in this study, which expresses JAKV617F under the regulatory control of the endogenous Jak2 locus, results in the onset of erythrocytosis and thrombocytosis within a number of weeks 10 and can be effectively transferred via bone marrow transplantation. 10 Mascarenhas et al found that if HSCs from the E11.5 AGM region were used as donor material, the expected pathology did not develop (no evidence of erythrocytosis or thrombocytosis was detected over a prolonged period of time and across 2 rounds of transplantation) and the DNA damage that characterizes adult JAKV617F cells was also absent.…”

2.1 Generation of Cell Lines and Biotechnological Applications

“…It was found that the MLL-AF9 fusion gene, which is predominantly associated with myeloid leukaemias, was able to immortalize this cell type. These cells are still able to differentiate either to the myeloid or to the lymphoid lineage [50].…”