Hierarchical distribution of somatic variants in newly diagnosed chronic myeloid leukaemia at diagnosis and early follow-up

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Authors	ROMŽOVÁ Marianna SMITALOVÁ Dagmar HYNŠT Jakub TOM Nikola LOJA Tomáš HERUDKOVÁ Zdeňka JURČEK Tomáš STEJSKAL Lukas ŽÁČKOVÁ Daniela MAYER Jiří RÁČIL Zdeněk ČULEN Martin
Year of publication	2021
Type	Article in Periodical
Magazine / Source	British journal of haematology
MU Faculty or unit	Central European Institute of Technology
Citation
web	https://onlinelibrary.wiley.com/doi/10.1111/bjh.17659
Doi	http://dx.doi.org/10.1111/bjh.17659
Keywords	CML; NGS; progenitors; leukaemic stem cells; somatic mutations; ASXL1
Description	There is an emerging body of evidence that patients with chronic myeloid leukaemia (CML) may carry not only breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue 1 (BCR-ABL1) kinase domain mutations (BCR-ABL1 KD mutations), but also mutations in other genes. Their occurrence is highest during progression or at failure, but their impact at diagnosis is unclear. In the present study, we prospectively screened for mutations in 18 myeloid neoplasm-associated genes and BCR-ABL1 KD in the following populations: bulk leucocytes, CD34(+)CD38(+) progenitors and CD34(+)CD38(-) stem cells, at diagnosis and early follow-up. In our cohort of chronic phase CML patients, nine of 49 patients harboured somatic mutations in the following genes: six ASXL1 mutations, one SETBP1, one TP53, one JAK2, but no BCR-ABL1 KD mutations. In seven of the nine patients, mutations were detected in multiple hierarchical populations including bulk leucocytes at diagnosis. The mutation dynamics reflected the BCR-ABL1 transcript decline induced by treatment in eight of the nine cases, suggesting that mutations were acquired in the Philadelphia chromosome (Ph)-positive clone. In one patient, the JAK2 V617F mutation correlated with a concomitant Ph-negative myeloproliferative neoplasm and persisted despite a 5-log reduction of the BCR-ABL1 transcript. Only two of the nine patients with mutations failed first-line therapy. No correlation was found between the mutation status and survival or response outcomes.
Related projects:	Mutační analýza primitivních buněčných populací u chronické myeloidní leukémie: za hranicí BCR-ABL1 Nové přístupy ve výzkumu, diagnostice a terapii hematologických malignit VIII