Impaired GBA1 or mitochondrial complex I activity leads to perturbation of lysosomal pH

Context: Lineage switch in acute leukemias (AL) is a rarely described entity. Several hypotheses have been proposed to explain it, notably the expansion of a coexisting subclone after suppression of the leukemic clone apparent at diagnosis by chemotherapy, alterations brought by chemotherapy upon the original clone, by suppressing differentiation programs, thus inducing a shift in phenotypic expression, or high fate plasticity of the hematopoietic progenitor cells, regulated by microenvironmental signals and transcription factors. Design: We report the case of a patient diagnosed with B-cell acute lymphoblastic leukemia, who relapsed after twelve months, with morphological and immunophenotypic findings consistent with acute monocytic leukemia. Results: An 18-year-old female presented to our clinic with a month-long history of fever, fatigue and menorrhagia. Upon clinical examination, hepatosplenomegaly and unilateral axillary adenopathy were found. Laboratory studies revealed severe pancytopenia with a white blood cell count of 1.6×109/L, hemoglobin value of 2.8 g/dL and platelet count of 30×109/L. Bone marrow (BM) examination showed an 80% lymphoblasts infiltrate, while the immunophenotypic analysis indicated B-cells positive for CD19, cCD79a, CD22, CD24, CD10, CD34, CD38, CD58, with dim expression of CD45, CD20, nuTdT, CD13, CD33, negative for myeloperoxidase (MPO) or markers of monocytic differentiation. No chromosomal or genetic abnormality was detected, including MLL gene rearrangement at 11q23, previously associated with lineage switch in AL. She was treated according to the GRAALL-2003 protocol and achieved complete remission. One year after the primary diagnosis, the BM aspirate showed a hypercellular marrow with 70% blasts, while flow cytometry identified expression of MPO, CD13, CD33 (bright), HLA-DR, CD14, CD15, CD56, CD38. She received chemotherapy with fludarabine, cytarabine and filgrastim, with failure in attaining remission, then followed a clofarabine, cytarabine and idarubicin regimen. At day +23, the BM aspirate showed normocellular marrow with 2-3% blast cells and a sibling hematopoietic stem-cell transplantation was planned, but three weeks later, the peripheral blood smear showed 43% blasts with monocytoid morphology. She is currently undergoing treatment with azacytidine and venetoclax. Conclusions: Despite tremendous advancements in the understanding of AL, many questions regarding the molecular mechanisms driving lineage switch need to be addressed. This rare phenomenon is associated with therapy resistance and poor clinical outcomes.