MLL-ENL-mediated leukemia initiation at the interface of lymphoid commitment

Abstract

Translocations involving the mixed lineage leukemia-1 are recurrent events in acute leukemia and associate with lymphoid (ALL), myeloid (AML) or mixed lineage (MLL) subtypes. Despite an association with ALL in humans, murine MLL fusion models are persistently restricted to AML. We here explored this issue using an inducible mixed lineage leukemia-eleven nineteen leukemia (MLL-ENL) mouse model. Although multiple progenitor cell types with myeloid potential are potent AML leukemia-initiating cells, also the earliest lymphoid progenitors were capable of initiating AML. This ability to evoke a latent myeloid potential in the earliest lymphoid progenitors was lost upon further lymphoid commitment. At the same time, more downstream/committed lymphoid precursors also failed to initiate lymphoid leukemia. Co-expression of MLL-ENL with a constitutively active RAS allele, the most common co-mutation in MLL fusion leukemias, could influence on both disease latency and lineage assignment of developing leukemia in what appears to be a mutation-order-dependent manner. Finally, CEBPB-mediated transdifferentation of committed and otherwise leukemia-incompetent B-cell progenitors imbued these cells with leukemic competence for AML. Therefore, apart from providing detailed insight into the differential responsiveness of candidate target cells to a first-hit MLL fusion event, our data warrants caution to therapeutic approaches based on the concept of transdifferentiation.

<p>T-lymphoid/myeloid mixed phenotype acute leukemia and early T-cell precursor lymphoblastic leukemia similarities with <em>NOTCH1</em> mutation as a good prognostic factor</p>

“…Kotrova et al, have demonstrated in ambiguous lineage leukemia with distinct T and M-blast populations the presence of typical T-ALL mutations that activate the NOTCH1 signaling pathway 27. In mice, aberrations such as KMT2A-ENL and KRASG12D cooperate to the rise of both AML and T-ALL 28. We have found one T/M-MPAL case with KMT2A-ENL, KRAS and NOTCH1 mutation that may be more consistent with Ugale’s animal model 28…”

“…In mice, aberrations such as KMT2A-ENL and KRASG12D cooperate to the rise of both AML and T-ALL 28. We have found one T/M-MPAL case with KMT2A-ENL, KRAS and NOTCH1 mutation that may be more consistent with Ugale’s animal model 28…”

Mouse models of MLL leukemia: recapitulating the human disease

“…35 In addition, unlike the Mll-Enl translocator model, 32 this DOX-inducible MLL-ENL produced only AML when expressed in T-cell progenitors. 51 More surprisingly, when they subfractionated the LSK compartment into granulocyte-monocyte-lymphoid progenitors, multipotent progenitors, and CD150 1 CD48 2 HSCs, only granulocyte-monocyte-lymphoid progenitors produced a transplantable AML. 50 MLL-ENL expressing HSCs not only failed to induce AML, they also displayed severely compromised reconstitution potential.…”

Immunoediting is not a primary transformation event in a murine model of MLL-ENL AML

“…Erythrocytes were sedimented with 1% dextran T500 (Sigma-Aldrich) and remaining erythrocytes were lysed with ACK (0.15 M NH 4 Cl, 10 mM KHCO 3 , and 0.1 mM EDTA; pH 7.2–7.4). The cells were stained and analyzed as described ( Ugale et al, 2017 ). The absolute lymphocyte counts were determined by multiplying the total white blood cell counts and the frequencies of B or T cells established by the FACS analysis.…”