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PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch.

ABSTRACT: Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A-rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A-MLLT3-rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A-MLLT3-rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre-post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia.

SUBMITTER: Nakajima K

PROVIDER: S-EPMC9277256 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundInfants with KMT2A-rearranged B-cell precursor acute lymphoblastic leukemia (ALL) have poor outcomes. There is an urgent need to identify novel agents to improve survival. Proteasome inhibition has emerged as a promising therapeutic strategy for several hematological malignancies. The aim of this study was to determine the preclinical efficacy of the selective proteasome inhibitor carfilzomib, for infants with KMT2A-rearranged ALL.MethodsEight infant ALL cell lines were extensively characterized for immunophenotypic and cytogenetic features. In vitro cytotoxicity to carfilzomib was assessed using a modified Alamar Blue assay with cells in logarithmic growth. The Bliss Independence model was applied to determine synergy between carfilzomib and the nine conventional chemotherapeutic agents used to treat infants with ALL. Established xenograft models were used to identify the maximal tolerated dose of carfilzomib and determine in vivo efficacy.ResultsCarfilzomib demonstrated low IC50 concentrations within the nanomolar range (6.0-15.8 nm) across the panel of cell lines. Combination drug testing indicated in vitro synergy between carfilzomib and several conventional chemotherapeutic agents including vincristine, daunorubicin, dexamethasone, L-asparaginase, and 4-hydroperoxycyclophosphamide. In vivo assessment did not lead to a survival advantage for either carfilzomib monotherapy, when used to treat both low or high disease burden, or for carfilzomib in combination with multi-agent induction chemotherapy comprising of vincristine, dexamethasone, and L-asparaginase.ConclusionsOur study highlights that in vitro efficacy does not necessarily translate to benefit in vivo and emphasizes the importance of in vivo validation prior to suggesting an agent for clinical use. Whilst proteasome inhibitors have an important role to play in several hematological malignancies, our findings guard against prioritization of carfilzomib for treatment of KMT2A-rearranged infant ALL in the clinical setting.

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PAX5 alterations in an infant case of KMT2A-rearranged leukemia with lineage switch.

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