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( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0377591 A1 Majeti Et Al US 20200377591A1 IN ( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2020/0377591 A1 Majeti et al . ( 43 ) Pub . Date : Dec. 3 , 2020 ( 54 ) MARKERS OF ACUTE MYELOID ( 60 ) Provisional application No. 61 / 011,324 , filed on Jan. LEUKEMIA STEM CELLS 15 , 2008 . ( 71 ) Applicant: The Board of Trustees of the Leland Publication Classification Stanford Junior University , Stanford , ( 51 ) Int . Ci . CA (US ) COZK 16/28 ( 2006.01 ) C12Q 1/6886 ( 2006.01 ) ( 72 ) Inventors: Ravindra Majeti, Palo Alto , CA ( US ) ; GOIN 33/50 ( 2006.01 ) Irving L. Weissman , Stanford , CA A61P 35/02 ( 2006.01 ) ( US ) GOIN 33/574 ( 2006.01 ) C12N 5/00 ( 2006.01 ) ( 21 ) Appl. No .: 16 / 853,319 C12N 5/09 ( 2006.01 ) CO7K 16/30 ( 2006.01 ) ( 22 ) Filed : Apr. 20 , 2020 ( 52 ) U.S. CI . CPC CO7K 16/2803 ( 2013.01 ) ; CO7K 16/2896 Related U.S. Application Data ( 2013.01 ) ; C12Q 1/6886 ( 2013.01 ) ; GOIN ( 63 ) Continuation of application No. 15 / 704,790 , filed on 33/5011 ( 2013.01 ) ; A61P 35/02 ( 2018.01 ) ; Sep. 14 , 2017 , now Pat . No. 10,662,242 , which is a A61K 2039/505 ( 2013.01 ) ; C12N 570093 continuation of application No. 14 / 927,349 , filed on ( 2013.01 ) ; C12N 5/0694 ( 2013.01 ) ; C07K Oct. 29 , 2015 , now Pat . No. 9,796,781 , which is a 16/28 ( 2013.01 ) ; CO7K 16/30 ( 2013.01 ) ; continuation of application No. 14 / 164,009 , filed on GO1N 33/5 7426 ( 2013.01 ) Jan. 24 , 2014 , now Pat . No. 9,193,955 , which is a ( 57 ) ABSTRACT continuation of application No. 13 / 739,788 , filed on Jan. 11 , 2013 , now Pat . No. 8,709,429 , which is a Markers of acute myeloid leukemia stem cells ( AMLSC ) are continuation of application No. 12 / 836,152 , filed on identified . The markers are differentially expressed in com Jul. 14 , 2010 , now Pat. No. 8,361,736 , which is a parison with normal counterpart cells , and are useful as continuation - in - part of application No. PCT /US09 / diagnostic and therapeutic targets. 00224 , filed on Jan. 13 , 2009 . Specification includes a Sequence Listing . Patent Application Publication Dec. 3 , 2020 Sheet 1 of 24 US 2020/0377591 A1 . CD45RA CD45RA FIGURE1 V ho CD34 CD34 Morewauog BloodCord Patent Application Publication Dec. 3 , 2020 Sheet 2 of 24 US 2020/0377591 A1 o *** ?? wit FIGURE2 Patent Application Publication Dec. 3 , 2020 Sheet 3 of 24 US 2020/0377591 A1 FIGURE3 *** Patent Application Publication Dec. 3 , 2020 Sheet 4 of 24 US 2020/0377591 A1 FIGURE4 Patent Application Publication Dec. 3 , 2020 Sheet 5 of 24 US2020'0377591A1 FIGURE5 ?? ? ??? ?8 ::: Patent Application Publication Dec. 3 , 2020 Sheet 6 of 24 US 2020/0377591 A1 FIGURE6 TransplantadPopulation 16 VolnodBajuMSUKIL. C 2:41 vokatoa1HEFOKU mun 00 Patent Application Publication Dec. 3 , 2020 Sheet 7 of 24 US 2020/0377591 A1 FIGURE7 PrimaryTransplant BuejasuolARUS A hCD45 of Myeloid PrimaryTransplant PrimaryTransplant 1 Chrism Human e o Patent Application Publication Dec. 3 , 2020 Sheet 8 of 24 US 2020/0377591 A1 FIGURE8 Patent Application Publication Dec. 3 , 2020 Sheet 9 of 24 US 2020/0377591 A1 aguaysajonig ueow B? CD47 A 9Figure Patent Application Publication Dec. 3 , 2020 Sheet 10 of 24 US 2020/0377591 A1 0 Figure10 Patent Application Publication Dec. 3 , 2020 Sheet 11 of 24 US 2020/0377591 A1 FIGURE11 35.2 3830 3S 0 ControlIsotype 390 SSO < Patent Application Publication Dec. 3 , 2020 Sheet 12 of 24 US 2020/0377591 A1 CD47anti- Control 12Figure wg up + EECO + Shaoy juajad Patent Application Publication Dec. 3 , 2020 Sheet 13 of 24 US 2020/0377591 A1 FIGURE13 . aguasjon ueow B? 6600 1 , A Patent Application Publication Dec. 3 , 2020 Sheet 14 of 24 US 2020/0377591 A1 . B? :: 2600 A? FIGURE14 Patent Application Publication Dec. 3 , 2020 Sheet 15 of 24 US 2020/0377591 A1 FIGURE15 25 CD34 CD47 CD47 MEP ?????? 130 FOYRIVI 10 1 CD34 137 LT-HSC CD47 CD47 FCRIVITI ** 49 0 BAR CD34 Lstionice-ka Axridad324 LOW 1 801-2oKagy+ CD34 Retin:beia RNABS KretredBM IIIIII ?????? ????? ?????? T T 18 fy BM bok2 healthy to Durparet .chotkj Foldi e Patent Application Publication Dec. 3 , 2020 Sheet 16 of 24 US 2020/0377591 A1 Asuminen woyu6030 wirineovisno FIGURE16 Patent Application Publication Dec. 3 , 2020 Sheet 17 of 24 US 2020/0377591 A1 FIGURE 17 2 Patent Application Publication Dec. 3 , 2020 Sheet 18 of 24 US 2020/0377591 A1 FIGURE18 WOO 2 111 Patent Application Publication Dec. 3 , 2020 Sheet 19 of 24 US 2020/0377591 A1 Figure . 33 i b of * Si .. ili FIGURE19 Patent Application Publication Dec. 3 , 2020 Sheet 20 of 24 US 2020/0377591 A1 StemCellsHematopoietic 42 FIGURE20 Patent Application Publication Dec. 3 , 2020 Sheet 21 of 24 US 2020/0377591 A1 CD34CD38+Lin 8 CD3-CD36CD90Lin“ FITX2043 FIGURE21 $ SampleType: ? WA CD34+CD38-CD90*Lin siisity?? b Patent Application Publication Dec. 3 , 2020 Sheet 22 of 24 US 2020/0377591 A1 ???????? 105 im blastcrisisCML FTC-AX:CD45R4 10 102 102 ???????? acceleratedphaseCML 4.88 FIGURE22 ????????????? 105 ????????? 104 TOTTITI Normal 10 ETC-AXCD45RA 52.2 CD45RA 105 %10 102 CD123 Patent Application Publication Dec. 3 , 2020 Sheet 23 of 24 US 2020/0377591 A1 sniawny-1 VW *** *n. FIGURE23 WM #t Patent Application Publication Dec. 3 , 2020 Sheet 24 of 24 US 2020/0377591 A1 ..... FIGURE24 . CD47 US 2020/0377591 A1 Dec. 3 , 2020 1 MARKERS OF ACUTE MYELOID some of the heterogeneity in tumors arises as a result of LEUKEMIA STEM CELLS continuing mutagenesis, it is likely that heterogeneity also arises through the aberrant differentiation of cancer cells . CROSS REFERENCE [ 0007 ] It is well documented that many types of tumors [ 0001 ] This application claims benefit and is a Continua contain cancer cells with heterogeneous phenotypes, reflect tion of application Ser . No. 15 / 704,790 filed Sep. 14 , 2017 , ing aspects of the differentiation that normally occurs in the which is a Continuation of application Ser. No. 14 / 927,349 tissues from which the tumors arise . The variable expression filed Oct. 29 , 2015 , now U.S. Pat . No. 9,796,781 issued Oct. of normal differentiation markers by cancer cells in a tumor 24 , 2017 , which is a Continuation of application Ser . No. suggests that some of the heterogeneity in tumors arises as 14 / 164,009 filed Jan. 24 , 2014 , now U.S. Pat . No. 9,193,955 a result of the anomalous differentiation of tumor cells . issued Nov. 24 , 2015 , which is a Continuation of application Examples of this include the variable expression of myeloid Ser . No. 13 / 739,788 filed Jan. 11 , 2013 , now U.S. Pat . No. markers in chronic myeloid leukaemia , the variable expres 8,709,429 issued Apr. 29 , 2014 , which is a Continuation of sion of neuronal markers within peripheral neurectodermal application Ser. No. 12 / 836,152 filed Jul. 14 , 2010 , now U.S. tumors , and the variable expression of milk proteins or the Pat . No. 8,361,736 issued Jan. 29 , 2013 , which is a Con estrogen receptor within breast cancer . tinuation in Part and claims the benefit of PCT Application [ 0008 ] It was first extensively documented for leukemia No. PCT /US2009 /000224 , filed Jan. 13 , 2009 , which claims and multiple myeloma that only a small subset of cancer benefit of U.S. Provisional Patent Application No. 61/011 , cells is capable of extensive proliferation. Because the 324 , filed Jan. 15 , 2008 , which applications are incorporated differences in clonogenicity among the leukemia cells mir rored the differences in clonogenicity among normal herein by reference in their entirety. hematopoietic cells , the clonogenic leukemic cells were FEDERALLY SPONSORED RESEARCH AND described as leukemic stem cells . It has also been shown for solid cancers that the cells are phenotypically heterogeneous DEVELOPMENT and that only a small proportion of cells are clonogenic in [ 0002 ] This invention was made with Government support culture and in vivo . Just as in the context of leukemic stem under contract CA086017 awarded by the National Institutes cells , these observations led to the hypothesis that only a few of Health . The Government has certain rights in this inven cancer cells are actually tumorigenic and that these tumori tion . genic cells act as cancer stem cells [ 0009 ] In support of this hypothesis , recent studies have BACKGROUND OF THE INVENTION shown that, similar to leukemia and other hematologic [ 0003 ] Basic cancer research has focused on identifying malignancies , tumorigenic and non -tumorigenic populations the genetic changes that lead to cancer. of breast cancer cells can be isolated based on their expres [ 0004 ] This has led to major advances in our understand sion of cell surface markers. In many cases of breast cancer , ing of the molecular and biochemical pathways that are only a small subpopulation of cells had the ability to form involved in tumorigenesis and malignant transformation . new tumors . This work strongly supports the existence of However, our understanding of the cellular biology has CSC in breast cancer. Further evidence for the existence of lagged . Although the effects of particular mutations on the cancer stem cells occurring in solid tumors has been found proliferation and survival of model cells , such as fibroblasts in central nervous system ( CNS ) malignancies. Using cul or cell lines , can be predicted, the effects of such mutations ture techniques similar to those used to culture normal on the actual cells involved in specific cancers is largely neuronal stem cells it has been shown that neuronal CNS guesswork . malignancies contain a small population of cancer cells that [ 0005 ] tumor can be viewed as an aberrant organ are clonogenic in vitro and initiate tumors in vivo , while the initiated by a tumorigenic cancer cell that acquired the remaining cells in the tumor do not have these properties .
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