We report a case of acute myeloid leukemia with megakaryoblastic differentiation (AMKL) that developed after an initial B-lymphoblastic leukemia (B-ALL) with low hypodiploidy. Although the AMKL was initially thought either to be a phenotypic change from the original B-ALL or to have arisen as a result of treatment (acute myeloid leukemia, post cytotoxic therapy, AML-pCT [WHO]; AML, therapy related [ICC]), genetic evaluation of both the AMKL and the B-ALL suggest that neither of these considerations was correct. Rather, the AMKL did not harbor the most common genetic hallmark of AML-pCT-rearrangement of KMT2- and was genetically distinct from the B-ALL. Both the B-ALL and the AMKL, however, showed an identical TP53 mutation by next generation sequencing (NGS), while germline testing was negative for this mutant allele. Hence, either the patient had a tissue restricted constitutional TP53 mutation or had a somatic mutation in a multipotent hematopoietic precursor. This case highlights the necessity for close monitoring of patients with TP53-mutant tumors, as they may develop multiple lesions despite negative germline testing.