Infant pro-B acute lymphoblastic leukemia (ALL) harboring MLL-AF4 fusion proteins instigated by chromosomal translocation t(4;11), represents an aggressive, high-risk type of childhood leukemia, characterized by a very brief disease latency and undisputedly originates in utero. Despite of recent advances and multiple important breakthroughs, MLL-AF4-driven leukemogenesis remains difficult to model and mouse models that accurately recapitulate the disease phenotype and latency are still lacking. Among several remarkable studies recently published, Montes et al. 1 demonstrated that enforced expression of MLL-AF4 in cord blood-derived hematopoietic stem cells (HSCs) increased the clonogenic potential of CD34+ progenitors and promoted proliferation, but appeared insufficient to induce leukemia. This study undeniably questions whether MLL-AF4 fusion proteins are capable of driving leukemogenesis on their own or whether additional genetic events are required such as RAS mutations 2. However, recent whole genome sequencing analysis in primary MLL-rearranged infant ALL samples revealed the presence of remarkably few somatic mutations 3. Contributing to the complexity of the matter, Bursen et al. 4 recently showed that introducing the reciprocal fusion protein AF4-MLL (resulting from the same balanced t(4;11) translocation), but not MLL-AF4, into murine hematopoietic stem/progenitor cells induced ALL in mice without the requirement of MLL-AF4. Nonetheless, these experiments have not yet been performed in human HSCs. Moreover, MLL-AF4 and AF4-MLL knockdown experiments have shown that t(4;11)-positive cell lines display addiction to MLL-AF4 (which appeared essential for leukemic cell proliferation and survival), but not to AF4-MLL 5. Thus, the AF4-MLL fusion protein may well be important or essential in the early transformation process and the MLL-AF4 fusion is certainly required for the maintenance of the leukemia. However, although the studies by Montes et al. 1 and Bursen et al. 4 seem to support that MLL-AF4 by itself is not sufficient to induce leukemogenesis in HSCs, others were able to induce lymphoid leukemias using MLL-AF4 knockin models in mice 2, 6. Yet, in these latter studies both the disease phenotye and latency of the observed leukemias appeared to deviate from the highly immature pro-B cell phenotype characteristically found in humans.