Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia by Ross Kinstrie, Dimitris Karamitros, Nicolas Goardon, Heather Morrison,

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Heterogeneous leukemia stem cells in myeloid blast phase chronic myeloid leukemia by Ross Kinstrie, Dimitris Karamitros, Nicolas Goardon, Heather Morrison, Mike Hamblin, Lisa Robinson, Richard E. Clark, Mhairi Copland, and Paresh Vyas BloodAdv Volume 1(3):160-169 December 27, 2016 © 2016 by The American Society of Hematology

Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Expansion of LMPP-, GMP-, MPP-, and CMP-like populations in myeloid BP-CML. Expansion of LMPP-, GMP-, MPP-, and CMP-like populations in myeloid BP-CML. Representative FACS plots of CD34+ enriched (A) normal bone marrow; (B) CP-CML; (C) AP-CML; myeloid BP-CML with (D) MPP-like and CMP-like populations; or (E) LMPP-like and GMP-like populations. Numbers of samples studied are shown on the right. Markers studied are shown below plots. Numbers in gates are the mean of all samples within the group expressed as a percentage of Lin−CD34+ cells. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Dynamic changes in immunophenotypic compartments in the progression from CP to BP-CML. Dynamic changes in immunophenotypic compartments in the progression from CP to BP-CML. (A) Bar graphs of mean sizes of indicated populations (x-axis) as a percentage of bone marrow Lin−CD34+ population (y-axis). Error bar corresponds to standard error of the mean: *P < .05; **P < .01; ***P < .001. (B) Tabular representation of the data in panel A. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Functional LSC activity in myeloid BP-CML. Functional LSC activity in myeloid BP-CML. (A) Purities of immunophenotypic populations (expressed as percentage), after FACS sorting, used in primary xenotransplantation from 5 patients (COL091, COL091R, CML371, CML002, and HER002). (B) Number of mice with human cell engraftment above engraftment threshold (defined as 0.1% human CD45+CD33+CD19− cells) out of the total number of mice injected. Myeloid engraftment or absence of engraftment is indicated. ND, nondetected. (C) Primary engraftment (4 patients: COL091, COL091R, CML371, and CML002, x-axis) in 1 to 6 mice from the indicated population. Black and red dots show the engraftment level in individual mice. y-axis: mean percentage human (h)CD45+CD33+CD19− cell engraftment/total live MNC. x-axis: injected cell fraction. Red line: engraftment threshold. (D) Number of human cells (y-axis) injected in primary mice from indicated population from 4 patients: COL091, CML371, COL091R, and CML002 (x-axis) in 1 to 6 mice. Black dots: engrafted mice. Red dots: mice that failed to engraft above the engraftment level of 0.1%. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Hierarchical relationships of normal HSPCs are not maintained in BP-CML. Hierarchical relationships of normal HSPCs are not maintained in BP-CML. (A) Percentage purities of population, after FACS sorting, injected for secondary transplant (Tx) from 2 patients (COL091, CML002). (B) Secondary engraftment of cells from 2 patients (COL091 and CML002). x-axis: bottom: patient sample populations injected into primary mice; top: population from primary engrafted mouse injected into secondary recipient. y-axis: mean percentage human (h)CD45+CD33+CD19− cell engraftment/total live MNC. Red line: engraftment threshold. Each dot represents 1 injected mouse: black dots: engrafted mice; red dots: mice that failed to engraft. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Clonal structures of stem/progenitor populations in myeloid BP-CML. Clonal structures of stem/progenitor populations in myeloid BP-CML. (A-C) Data from patients CML002, COL091, and COL091R. Clone identities denoted by circles or bars. (i) Immunophenotypic HSPC populations in patient sample. y-axis: proportion of population as percentage of Lin−CD34+ cells. (ii) Clonal composition of purified patient populations is based on FISH analysis. x-axis: HSPC population. y-axis: frequency of clones per population. (iii) Clonal hierarchies inferred from FISH data. (D) FISH images: ABL (red); BCR (green); BCR-ABL fusion (F); p53/17p13 (gold); MPO/17q22 (aqua). Atypical BCR-ABL is defined by 1 or 3 BCR-ABL fusions. 17p13 loss is defined by p53 loss. Isochrosome 17q is defined by 3 MPO signals. Numbers of signals detected are indicated. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology

Analysis of clonal structures in NSG mice after transplantation of stem/progenitor populations. Analysis of clonal structures in NSG mice after transplantation of stem/progenitor populations. Frequency and type of leukemic clones in individual engrafted mice. Injected populations indicated. Results from 1° (A, B, C) and 2° transplantation (A and B) are shown. BM, bone marrow; NA, cells unavailable for FISH analysis. Ross Kinstrie et al. Blood Adv 2016;1:160-169 © 2016 by The American Society of Hematology