Homeodomain-only protein homeobox (HOPX) is the smallest homeodomain protein. It was regarded as a stem cell marker in several non-hematopoietic systems. While the prototypic homeobox genes such as the HOX family have been well characterized in acute myeloid leukemia (AML), the clinical and biological implications of HOPX in the disease remain unknown. Thus we analyzed HOPX and global gene expression patterns in 347 newly diagnosed de novo AML patients in our institute. We found that higher HOPX expression was closely associated with older age, higher platelet counts, lower white blood cell counts, lower lactate dehydrogenase levels, and mutations in RUNX1, IDH2, ASXL1, and DNMT3A, but negatively associated with acute promyelocytic leukemia, favorable karyotypes, CEBPA double mutations and NPM1 mutation. Patients with higher HOPX expression had a lower complete remission rate and shorter survival. The finding was validated in two independent cohorts. Multivariate analysis revealed that higher HOPX expression was an independent unfavorable prognostic factor irrespective of other known prognostic parameters and gene signatures derived from multiple cohorts. Gene set enrichment analysis showed higher HOPX expression was associated with both hematopoietic and leukemia stem cell signatures. While HOPX and HOX family genes showed concordant expression patterns in normal hematopoietic stem/progenitor cells, their expression patterns and associated clinical and biological features were distinctive in AML settings, demonstrating HOPX to be a unique homeobox gene. Therefore, HOPX is a distinctive homeobox gene with characteristic clinical and biological implications and its expression is a powerful predictor of prognosis in AML patients.

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Plant homeodomain finger gene 6 (PHF6) encodes a 365-amino-acid protein containing 2 plant homology domain fingers. Germline mutations of human PHF6 cause Börjeson-Forssman-Lehmann syndrome, a congenital neurodevelopmental disorder. Loss-of-function mutations of PHF6 are detected in patients with acute leukemia, mainly of T-cell lineage and in a small proportion of myeloid lineage. The functions of PHF6 in physiological hematopoiesis and leukemogenesis remain incompletely defined. To address this question, we generated a conditional Phf6 knockout mouse model and investigated the impact of Phf6 loss on the hematopoietic system. We found that Phf6 knockout mice at 8 weeks of age had reduced numbers of CD4+ and CD8+ T cells in the peripheral blood compared with the wild-type littermates. There were decreased granulocyte-monocytic progenitors but increased Lin–c-Kit+Sca-1+ cells in the marrow of young Phf6 knockout mice. Functional studies, including competitive repopulation unit and serial transplantation assays, revealed an enhanced reconstitution and self-renewal capacity in Phf6 knockout hematopoietic stem cells (HSCs). Aged Phf6 knockout mice had myelodysplasia-like presentations, including decreased platelet counts, megakaryocyte dysplasia, and enlarged spleen related to extramedullary hematopoiesis. Moreover, we found that Phf6 loss lowered the threshold of NOTCH1-induced leukemic transformation at least partially through increased leukemia-initiating cells. Transcriptome analysis on the restrictive rare HSC subpopulations revealed upregulated cell cycling and oncogenic functions, with alteration of key gene expression in those pathways. In summary, our studies show the in vivo crucial roles of Phf6 in physiological and malignant hematopoiesis.

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Background: Letermovir prophylaxis is currently the standard of care for the prevention of cytomegalovirus (CMV) infections in allogeneic hematopoietic stem-cell transplantation (allo-HSCT). However, drug–drug interactions between letermovir and azoles or calcineurin inhibitors and the high financial burden of letermovir remain problematic, especially in resource-limited countries. It has not been clarified whether a lower dose of valganciclovir would constitute an effective strategy for CMV prevention in patients with acute leukemia undergoing allo-HSCT. Methods: We retrospectively assessed 84 consecutive adult patients with acute leukemia who underwent allo-HSCT. These 84 patients were stratified into a valganciclovir prophylaxis group ( n = 20) and a non-valganciclovir prophylaxis group ( n = 64). Results: Patients in the valganciclovir prophylaxis group had a lower possibility of CMV DNAemia at week 14 after allo-HSCT than those in the non-valganciclovir prophylaxis group (15.0% versus 50.0%; p = 0.012). The cumulative incidence of CMV DNAemia at week 14 was also lower in patients with valganciclovir CMV prophylaxis than in those without (15.0% versus 50.4%; p = 0.006). Multivariate analysis validated these data, showing that a low dose of valganciclovir significantly reduced the risk of CMV DNAemia at week 14 by 88% (hazard ratio: 0.12; 95% confidence interval: 0.04–0.42; p = 0.001). However, these two groups had similar overall survival rates at week 48 (75.0% versus 76.6%; p = 0.805). Four of 20 (20%) patients discontinued valganciclovir prophylaxis because of adverse events. Conclusion: Low-dose valganciclovir prophylaxis could be an alternative to letermovir to prevent CMV infection in allo-HSCT, especially in resource-limited countries.

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Background: Posaconazole prophylaxis during remission induction chemotherapy not only decreases the incidence of invasive aspergillosis (IA) but also improves the overall survival rate among patients with acute myeloid leukemia (AML). However, it remains debatable whether this result applies to patients in a real-world setting. Methods: We retrospectively assessed 208 adult patients with newly diagnosed AML who underwent remission induction therapy. These 208 patients were stratified into the posaconazole prophylaxis group ( n = 58) and no antifungal prophylaxis group ( n = 150). Results: Multivariate analyses showed that induction failure significantly increased the risk of proven or probable IA during the first induction chemotherapy [hazard ratio (HR), 10.47; 95% confidence interval (CI), 1.73–63.45; p = 0.011] and the entire course of AML treatment (HR, 4.48; 95% CI, 1.71–11.75; p = 0.002). However, posaconazole prophylaxis did not reduce the risk of IA during the first induction chemotherapy (HR, 1.47; 95% CI, 0.14–15.04; p = 0.746) and during the entire course of AML treatment (HR, 1.09; 95% CI, 0.29–4.09; p = 0.896). Furthermore, there was no significant difference in overall survival between these two groups of patients (514 versus 689 days; p = 0.454). Conclusion: Successful induction remains fundamental to reducing the risk of IA among AML patients undergoing remission induction chemotherapy.

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