(b).

Human models	Method	Phenotype of leukemia	Features	References
Xenograft nude mice	Nude mice injected with K562	K562 grew as solid vascularized tumors	Tumor cells were triphoid and retined human chromosome markers	[43]
Xenograft nude mice	SIA-nu/nu mice were injected with leukemic cell lines and primary patient sample	K562 formed solid tumor at challenged site without metastatic spread with mean latency of 10 days	6/8 leukemic cell lines and 5/18 primary neoplastic tumors induced serially transplantable solid soft mass	[44]
Xenograft SCID mice	BM samples of CP-CML and BC-CML as well as cell lines; K562 and EM-2 were transplanted into CB-17 scid/scid mice	All mice injected with K562 as well as EM-2 or primary CP-CML and BC-CML samples by IV or IP engraft to give myeloblasts in BM, blood, and tumors in peritoneum	After initial growth in kidney capsule, myeloblasts were detected at varying levels in PB and BM. Human myeloid and lymphoid leukemia cell lines showed distinct growth patterns. Differences were also observed in engraftment of CP versus BC-CML primary patient samples	[45]
Xenograft SCID mice	BM or PB samples obtained from CP-CML and BC-CML patients were injected by IV into sublethally irradiated [400 cGy] SCID mice. Exogenous cytokines PIXY321 or c-kit ligand was injected IP	CP-CML and BC-CML patient sample showed 1–>10% engraftment with 30–60 days of latency in presence or absence of exogenous human cytokines	Multilineage engraftment and CD34+ cells were maintained for more than 60 days after transplantation. First evidence that both normal and leukemic CP-CML cells can engraft in SCID mice	[46]
Xenograft NOD/SCID	MNCs from apheresis material from CML patient were IV transplanted into sublethally irradiated [300 cGy] NOD/SCID mice. Preselected CD34+ and CD34− cells were also used for BM engrafted studies	≥1–84% multilineage engraftment observed in BM in 76% mice and only 66% of mice showed 16% predominantly T cell splenic engraftment. CML-like disease in BM and spleen. 39%  ±  5% leukemic engraftment in 25 mice having ≥9% BM engraftment was higher as compared to BCR-ABL engraftment in spleen	Higher engraftment in NOD/SCID mice using low cell dose compared to SCID mice	[47]
Xenograft NOD/SCID	MNCs or CD34+ enriched cells from BM or PB of 11 CP-CML patient were IV transplanted into sublethally irradiated [400 cGy] NOD/SCID mice	25% of NOD/SCID recipients had 40–80% human cells, whereas only 3% SCID mice contained similar levels. Further, engrafted human cells had high proportion of leukemic cells along with CD34+ cells	NOD/SCID mice allow greater engraftment and amplification of both normal and leukemic cells as compared to SCID mouse model	[48]
Xenograft NOD/SCID	BV173 and PB MN cells from CP, AP, and BC CML patient samples were injected	Kinetics and extent of engraftment BP > AP > CP, although according to growth rate BP > AP ≥ CP	Kinetics of BM repopulation are different for CP, AP, and BC phase of CML	[49]
Xenograft NOD/SCID	9 CP-CML patient samples with predominant LTC-IC were transplanted into sublethally irradiated [350 cGy] NOD/SCID and NOD/SCID β2m−/− mice	Consistent and durable engraftment was observed with reduced output of B cells and enhanced myelopoiesis with excessive production of erythroid, megakaryocytes, and BCR-ABL CD34+ expressing IL-3 and G-CSF transcripts	No progressive disease phenotype was observed marking CP-CML phase of the disease	[8]
Xenograft NOD/SCID	CB CD34+ cells were transduced with MSCV based retroviral constructs for BCR-ABL and transplanted 0.2 to 0.3 million cells into each sublethally irradiated [350 cGy] NOD/SCID and NOD/SCID β2m−/− mice	BCR-ABL transduced cells produced increased ratio of myeloid to B-lymphoid cells with increase in erythroid and megakaryocytic cells. 4/28 mice developed an increased WBC count and/or splenomegaly after 5-6 months of latency	First ever model to describe the de novo generation of preleukemic cells by forced expression of BCR-ABL in human CD34+ CB cells. Primary CD34+ CB cells showed rapid and persistent deregulation and erythroid and megakaryocytic biased differentiation in vivo with occasional progression to an early stage of CML	[50]
Xenograft NOD/SCID	CB CD34+ cells were transduced with MSCV based retroviral constructs for BMI1 and BCR-ABL and transplanted only 0.46 to 0.38 million cells into each sublethally irradiated [3 Gy] NOD/SCID mice	4/8 mice succumbed to [CD34+ CD19+] B-ALL in 16–22 weeks on transplantation of CD34+ cells cotransduced with BMI/BCR-ABL and all secondaries came down with similar phenotypes within 8–12 weeks	Coexpression of BMI1 and BCR-ABL in CB CD34+ cells is sufficient to induce transplantable B-ALL in NOD/SCID mice	[51]
iPSC	KBM7 cells were reprogrammed by retroviral transduction of OCT4, SOX2, c-MYC, and KLF-4	Teratoma formation and imatinib resistance were observed	The process of reprogramming KBM7 cell lines readily abolished BCR-ABL dependency which was restored by differentiation into hematopoietic lineage	[52]
iPSC	MNCs from BM of CP-CML patient sample were cultured with human SCF, IL-3, IL-6, and Flt3L for 2 days and transfected with episomal vectors by nucleofection	CP-CML iPSC lines generated exhibited features of pluripotent stem cells, exhibited complex karyotype, and differentiated into hematopoietic lineages	Transgene free CML iPSC lines can be obtained	[53]
iPSC	Regeneration of CML iPSCs from CD34+ BM MNCs of CP-CML patient sample by retroviral vectors	DNA methylation pattern and gene expression profile of CML-iPSCs were different from those of original CML sample but were similar to normal iPSCs and human ES cells	Recapitulation of CP CML was shown in terms of that fraction of phenotypically immature cells which showed imatinib resistance although more differentiated cells recovered the sensitivity to imatinib	[54]