Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Leukemic IDH1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPC): Experimental Evidences and a Review of the Literature

Sara Pierangeli
,
Serena Donnini
,
Valerio Ciaurro
,
Francesca Milano
,
Valeria Cardinali
,
Sofia Sciabolacci
,
Gaetano Cimino
ORCID logo ,
Ilaria Gionfriddo
,
Roberta Ranieri
,
Sabrina Cipriani
,
Eleonora Padiglioni
ORCID logo ,
Roberta Iacucci Ostini
,
Tiziana Zei
,
Antonio Pierini
,
Maria Paola Martelli
* ORCID logo
Version 1 : Received: 24 June 2024 / Approved: 25 June 2024 / Online: 25 June 2024 (10:10:07 CEST)

How to cite: Pierangeli, S.; Donnini, S.; Ciaurro, V.; Milano, F.; Cardinali, V.; Sciabolacci, S.; Cimino, G.; Gionfriddo, I.; Ranieri, R.; Cipriani, S.; Padiglioni, E.; Iacucci Ostini, R.; Zei, T.; Pierini, A.; Martelli, M. P. The Leukemic IDH1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPC): Experimental Evidences and a Review of the Literature. Preprints 2024, 2024061723. https://doi.org/10.20944/preprints202406.1723.v1 Pierangeli, S.; Donnini, S.; Ciaurro, V.; Milano, F.; Cardinali, V.; Sciabolacci, S.; Cimino, G.; Gionfriddo, I.; Ranieri, R.; Cipriani, S.; Padiglioni, E.; Iacucci Ostini, R.; Zei, T.; Pierini, A.; Martelli, M. P. The Leukemic IDH1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPC): Experimental Evidences and a Review of the Literature. Preprints 2024, 2024061723. https://doi.org/10.20944/preprints202406.1723.v1

Abstract

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we studied isocitrate dehydrogenases (IDH) genes mutations in the human model of HSPC and provide a review of the literature on this topic. IDH1/2 mutations occur in ~20% of AML, are recognized among the mutations earliest acquired during leukemogenesis, and are target of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on the HSPC we expressed by lentiviral transduction either IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by the specific inhibitors, confirming it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed over time a progressive and marked improvement of their fitness in terms of CFU ability and propensity to differentiate, attaining clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Keywords

acute myeloid leukemia; IDH1/2 mutation; human HSPC modeling

Subject

Medicine and Pharmacology, Hematology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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