In this issue, a nationwide retrospective Japanese study finds that, in a second opinion setting, one‐third of bone marrow aspirates from patients suspected of myelodysplastic syndromes are heavily ...haemodiluted. Moreover, in four‐fifths of such cases, the failure to obtain the correct material for diagnosis went undetected by the referring institution. These data are intriguing, but given their special set‐up, caution should be exerted in transposing them to other countries.
Commentary on: Ogata et al. Prevalence of massively diluted bone marrow cell samples aspirated from patients with myelodysplastic syndromes (MDS) or suspected MDS: A retrospective analysis of nationwide samples in Japan. Br J Haematol 2024;204:1856‐1861.
Rounding off our Global View series Hokland, Peter
British journal of haematology,
December 2023, 2023-12-00, 20231201, Letnik:
203, Številka:
5
Journal Article
Recenzirano
Odprti dostop
In this issue, we publish the last instalment in our series ‘Global View’ within the ‘Wider Perspective’ umbrella. In it we query experts from a variety of countries—deliberately trying to encompass ...both those with strained economies as well as more affluent ones—as to how patients are handled within such widely varying health systems.
Commentary on: Hokland et al. AML in the elderly—A global view. Br J Haematol 2023;203:760–773.
MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast ...crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA's seed sequence and it leads to release of
CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.
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► Expression of miR-328 is reduced in CD34
+ CML blast crisis (CML-BC) progenitors ► miR-328 directly binds hnRNP E2 and rescues
CEBPA mRNA translation ► miR-328 restores C/EBPα-dependent maturation of myeloid CML-BC progenitors ► miR-328 pairs with
PIM1 3′UTR and impairs survival of CML-BC progenitors
AML — a signature disease in haematology Hokland, Peter
British journal of haematology,
January 2020, 2020-Jan, 2020-01-00, 20200101, Letnik:
188, Številka:
1
Journal Article
As tyrosine kinase inhibitors (TKIs) fail to induce long-term response in blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia ...(ALL), novel therapies targeting leukemia-dysregulated pathways are necessary. Exportin-1 (XPO1), also known as chromosome maintenance protein 1, regulates cell growth and differentiation by controlling the nucleocytoplasmic trafficking of proteins and RNAs, some of which are aberrantly modulated in BCR-ABL1+ leukemias. Using CD34+ progenitors from CML, B-ALL, and healthy individuals, we found that XPO1 expression was markedly increased, mostly in a TKI-sensitive manner, in CML-BC and Ph+ B-ALL. Notably, XPO1 was also elevated in Ph− B-ALL. Moreover, the clinically relevant XPO1 inhibitor KPT-330 strongly triggered apoptosis and impaired the clonogenic potential of leukemic, but not normal, CD34+ progenitors, and increased survival of BCR-ABL1+ mice, 50% of which remained alive and, mostly, became BCR-ABL1 negative. Moreover, KPT-330 compassionate use in a patient with TKI-resistant CML undergoing disease progression significantly reduced white blood cell count, blast cells, splenomegaly, lactate dehydrogenase levels, and bone pain. Mechanistically, KPT-330 altered the subcellular localization of leukemia-regulated factors including RNA-binding heterogeneous nuclear ribonucleoprotein A1 and the oncogene SET, thereby inducing reactivation of protein phosphatase 2A tumor suppressor and inhibition of BCR-ABL1 in CML-BC cells. Because XPO1 is important for leukemic cell survival, KPT-330 may represent an alternative therapy for TKI-refractory Ph+ leukemias.
•XPO1/CRM1 is upregulated in a BCR-ABL1 kinase-dependent and -independent manner and negatively controls PP2A tumor suppressor activity.•KPT-330 antagonizes survival of TKI-resistant Ph+ acute leukemias in vitro, in CML-BC animals, and in a CML-AP patient.
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