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000294687 1001_ $$0P:(DE-He78)48b15f8f3a2bfd2cb3153cd0aa1d631f$$aLeppä, Aino-Maija$$b0$$eFirst author$$udkfz
000294687 245__ $$aSingle-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.
000294687 260__ $$aLondon$$bMacmillan Publishers Limited, part of Springer Nature$$c2024
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000294687 520__ $$aChromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.
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000294687 7001_ $$00000-0002-4805-2366$$aGrimes, Karen$$b1
000294687 7001_ $$00000-0002-1526-3343$$aJeong, Hyobin$$b2
000294687 7001_ $$0P:(DE-He78)d2bcf2be29a87661e60b01f83511fe53$$aHuang, Frank Yi-Tao$$b3$$udkfz
000294687 7001_ $$aAndrades, Alvaro$$b4
000294687 7001_ $$0P:(DE-He78)768417e724d181a1038be1868c5d5412$$aWaclawiczek, Alexander$$b5$$udkfz
000294687 7001_ $$aBoch, Tobias$$b6
000294687 7001_ $$aJauch, Anna$$b7
000294687 7001_ $$0P:(DE-He78)59008c47a42b433b0328d0043b656ed2$$aRenders, Simon$$b8$$udkfz
000294687 7001_ $$0P:(DE-He78)839d6df226dd097c1b503e3e7fa20c87$$aStelmach, Patrick$$b9$$udkfz
000294687 7001_ $$aMüller-Tidow, Carsten$$b10
000294687 7001_ $$0P:(DE-He78)a6fa84be04bffac56f1c2dc5abe99775$$aKarpova, Darja$$b11
000294687 7001_ $$0P:(DE-He78)39965117aef10b17055de724893accee$$aSohn, Markus$$b12$$udkfz
000294687 7001_ $$0P:(DE-He78)6b879b5f67d8b3bcdffc7c01cbf8d1f1$$aGrünschläger, Florian$$b13$$udkfz
000294687 7001_ $$aHasenfeld, Patrick$$b14
000294687 7001_ $$aBenito Garagorri, Eva$$b15
000294687 7001_ $$0P:(DE-He78)6e9ce2232245f76dc483333cba4a5b91$$aThiel, Vera$$b16$$udkfz
000294687 7001_ $$00000-0003-4166-2900$$aDolnik, Anna$$b17
000294687 7001_ $$aRodriguez-Martin, Bernardo$$b18
000294687 7001_ $$00000-0002-5890-5510$$aBullinger, Lars$$b19
000294687 7001_ $$00000-0002-1408-5063$$aMrózek, Krzysztof$$b20
000294687 7001_ $$00000-0001-6442-1419$$aEisfeld, Ann-Kathrin$$b21
000294687 7001_ $$0P:(DE-He78)493c5fbf69f1b20df6f048712f3ad4a0$$aKrämer, Alwin$$b22$$udkfz
000294687 7001_ $$00000-0003-3945-0677$$aSanders, Ashley D$$b23
000294687 7001_ $$0P:(DE-He78)372b77c2acf8604690a6a325a4e89287$$aKorbel, Jan$$b24$$eLast author$$udkfz
000294687 7001_ $$0P:(DE-He78)732f4fbcddb0042251aa759a2e74d3b2$$aTrumpp, Andreas$$b25$$eLast author$$udkfz
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