PHKA2-AS1 promotes leukemic proliferation and is associated with poor prognosis in acute myeloid leukemia

Acute myeloid leukemia remains a highly aggressive hematological malignancy with poor clinical outcomes. Long non-coding RNAs are increasingly recognized as regulators of leukemia biology, but the role of PHKA2-AS1 in AML remains unclear. MCOLN1-related lysosome–mitochondria stress and zinc homeostasis have been implicated in cancer cell fate; however, whether AML-associated lncRNAs are transcriptionally associated with this axis has not been fully explored. We integrated public transcriptomic analyses with in vitro and in vivo assays to evaluate the clinical relevance and biological effects of PHKA2-AS1 in AML. PHKA2-AS1 expression, subcellular localization, and functional effects were examined using qRT-PCR, FISH, nuclear/cytoplasmic fractionation, proliferation, cell-cycle, apoptosis, and xenograft assays. Correlations between PHKA2-AS1 and MCOLN1 or mitochondrial stress-related genes were assessed as exploratory co-expression analyses. PHKA2-AS1 was upregulated in AML in public transcriptomic analyses and in local bone marrow samples, and it was predominantly localized in the nucleus. PHKA2-AS1 overexpression promoted MV4-11 cell proliferation, facilitated G1/S cell-cycle transition, and showed a trend toward increased xenograft tumor growth, whereas its effect on apoptosis was limited. In the TCGA-LAML cohort, higher PHKA2-AS1 expression was associated with poorer overall survival and showed weak-to-moderate correlations with MCOLN1 and several mitochondrial stress-related genes, including BID, CASP9, and PINK1. An internally assessed exploratory PHKA2-AS1-related lncRNA prognostic signature showed apparent within-cohort prognostic performance in TCGA-LAML; however, no external or additional resampling-based validation was performed. Computational immune analyses suggested differences in immune-related transcriptional signatures between groups stratified by PHKA2-AS1 expression or risk score. PHKA2-AS1 is upregulated in AML, associated with shorter overall survival in the TCGA-LAML cohort, and promotes leukemic proliferation in the models examined. Its co-expression with MCOLN1 and mitochondrial stress-related genes suggests a potential lysosome–mitochondria stress-related transcriptional context, providing a rationale for future mechanistic studies.