TY - JOUR
T1 - Stem cell mutations can be detected in myeloma patients years before onset of secondary leukemias
AU - Sridharan, Ashwin
AU - Schinke, Carolina D.
AU - Georgiev, George
AU - da Silva Ferreira, Mariana
AU - Thiruthuvanathan, Victor
AU - MacArthur, Ian
AU - Bhagat, Tushar D.
AU - Choudhary, Gaurav S.
AU - Aluri, Srinivas
AU - Chen, Jiahao
AU - Pradhan, Kith
AU - Xia, Yu
AU - Panjikaran, Maya
AU - Sims, Gregory
AU - Bhagat, Chirag K.
AU - Bender, Ryan
AU - Keeler, Lauryn
AU - Graber, Armin
AU - Heuck, Christoph
AU - Fletcher, Frederick A.
AU - Alapat, Daisy
AU - Weinhold, Niels
AU - Johnson, Sarah K.
AU - Wickrema, Amittha
AU - Barlogie, Bart
AU - Morgan, Gareth J.
AU - Shastri, Aditi
AU - Steidl, Ulrich
AU - Will, Britta
AU - Verma, Amit
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019
Y1 - 2019
N2 - Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.
AB - Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/t-MDS) are secondary hematologic malignancies associated with poor prognosis, warranting insights into their predisposing conditions and cells of origin. We identified patients with myeloma who developed t-AML/t-MDS and analyzed their stem and progenitor cells collected years before the onset of secondary disease. We demonstrate that aberrant stem cells with high CD123 expression can be detected long before the onset of overt leukemia. Rigorous sorting, followed by targeted sequencing, resulted in ultradeep functional depth of sequencing and revealed preexisting mutant hematopoietic stem cell (HSC) clones, mainly harboring TP53 mutations, that became the dominant population at the time of leukemic presentation. Taken together, these data show that HSCs can act as reservoirs for leukemia-initiating cells many years before the onset of myeloid leukemia.
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U2 - 10.1182/bloodadvances.2019000731
DO - 10.1182/bloodadvances.2019000731
M3 - Article
C2 - 31805192
AN - SCOPUS:85076359715
SN - 2473-9529
VL - 3
SP - 3962
EP - 3967
JO - Blood Advances
JF - Blood Advances
IS - 23
ER -