Leukemia development efforts using human HSPC and in vivo analyses
| Gene(s) . | Reference . | Key findings . | Cell source . | Mice used . |
|---|---|---|---|---|
| TLS-ERG | 143 | Increased myeloid progenitors with serial replating and increased proliferation, decreased erythroid progenitors, increased lifespan of myeloid cells in culture. No engraftment in mice. | UCB CD34+ lin− | NS |
| HoxA10 | 144 | Increased CFCs from in vitro cultures, block of erythroid differentiation. Engraftment skewed to myeloid in vivo, enriched for transduced cells. | UCB lin−, FL | NS |
| AML1-ETO | 145 | Clonal long-term culture of myeloid cells that retain multilineage potential, CFU-Cs, CAFC activity. Very low levels of human engraftment in mice. | UCB/PBPC CD34+ | NS |
| STAT5A(1*6) | 146 | Increased proliferation of mostly erythroid progenitors, long-term CAFC cultures. Low levels of mostly erythroid lineage engraftment in mice. | UCB CD34+ | NS |
| NRAS(G12D) | 147 | Increased proliferation, cell cycle, increased myeloid differentiation with reduced B and erythroid differentiation in vitro. Improved myeloid skewed multilineage engraftment in mice. | UCB CD34+ | NS |
| TLS-ERG | 148 | Increased proliferation and lifespan, expansion of myeloid progenitors, incomplete myeloid differentiation. One immortalized line with high CD34+ and multilineage potential. Transient engraftment in mice. | UCB lin− | NS |
| BCR-ABL(p210) | 149 | Reduced myeloid colonies and increased erythroid colonies in vitro. A portion of engrafted mice showed myeloproliferation with increasing glyA positivity over time. | UCB lin− | NS, NS-B2M |
| CBFB-MYH11 | 150 | Clonal expansion of myelomonocytic cells with eosinophilia and increased lifespan in vitro with reduced erythroid and B cell potential. Long-term cultures retain modest myeloid restricted engraftment of mice. | UCB CD34+ | NS-B2M |
| TEL-JAK2 | 151 | Increased proliferation and expansion of myeloid and erythroid cells in vitro. Mice engrafted similar to controls, but grafts skewed toward myeloid and erythroid lineages. Myelofibrosis induced in TEL-JAK2 mice. | UCB lin− | NS |
| NUP98-HoxA9 | 152 | Increased expansion, decreased erythroid colonies, increased secondary myeloid colonies, more CAFCs. Proliferative advantage of transduced cells in engrafted mice. | UCB CD34+ | NS, NS-B2M, NSG |
| MLL-AF9 | 94 | Increased lifespan in vitro. pre-B ALL in 8/16 mice, AML in 2/16, mixed lineage in 1/16. | UCB lin− | NS |
| MLL-ENL | 94 | Increased lifespan in vitro. pre-B ALL in vivo. | UCB lin− | NS |
| MLL-AF9 | 93 | Immortal myeloid and lymphoid cultures. B ALL in NS and NS-B2M mice and AML in NSS mice. | UCB CD34+ | NS, NS-B2M, NSS |
| BMI1 | 74 | Enhanced self-renewal (CAFC, LTC-IC) in vitro. Improved engraftment in primary and secondary (very low) mice. | UCB CD34+ | NS |
| TEL-AML1 | 120 | Serial engraftment of an abnormal CD34+CD38-CD19+ cell population, potentially containing pre-LSCs. | UCB CD34+ | NS |
| BCR-ABL+BMI1 | 95 | Increased proliferation, self-renewal (CAFC) in vitro. B-ALL generated in 4/8 mice, transplantable. | UCB CD34+ | NS |
| MLL-AF9+NRAS(G12D) | 9 | Cytokine independent growth in vitro. Faster development of AML in vivo (relative to MLL-AF9 alone), engrafts non-conditioned hosts. | UCB CD34+ | NS, NSG, NSS, NSGS |
| AML1-ETO+NRAS(G12D) | 153 | Increased culture lifespan, serial methylcell replating with erythroid to myeloid shift, cytokine independent growth in vitro. Improved engraftment over AE alone, subcutaneous tumors. | UCB CD34+ | NSG, NSGS |
| MLL-AF9+FLT3-ITD | 103 | Cytokine independent growth in vitro. Faster development of AML in vivo (relative to MLL-AF9 alone), engrafts non-conditioned hosts. | UCB CD34+ | NSG, NSGS |
| BCR-ABL+Ikaros | 92 | Proliferative advantage in vitro. Slight lifespan increase, skewed to erythroid, loss of B cell potential. Expansion of myeloid and erythroid cells in mice. Aggressive AML with disseminated myeloid sarcomas within four weeks; not transplantable. | UCB lin− | NSG, NSGS |
| ERG | 154 | Improved engraftment of transduced cells in thymus of mice, no difference otherwise. | UCB CD34+ | NSG |
| AML1-ETO+c-Kit | 155 | Increased expansion over AE alone, c-kit attenuates AE-induced DNA damage, transient and low levels of human engraftment in mice. | PBPC CD34+ | NSG |
| NUP98-HOXD13+MN1 | 156 | Transient, non-transplantable myeloproliferation with MN1 alone. Aggressive and transplantable AML with NUP98-HoxD13+MN1 only in NSGS mice. | UCB CD34+ | NSG, NSGS |
| PML-RARA | 157 | Reduced myeloid and erythroid colonies in vitro. Sorted CD34+CD38+, but not CD34+CD38- UCB cells led to myeloid skewed engraftment in NOG mice with several abnormal characteristics of APL cells. Low secondary transplantation from unsorted or CD34- cells. | UCB CD34+ | NOG |
| Gene(s) . | Reference . | Key findings . | Cell source . | Mice used . |
|---|---|---|---|---|
| TLS-ERG | 143 | Increased myeloid progenitors with serial replating and increased proliferation, decreased erythroid progenitors, increased lifespan of myeloid cells in culture. No engraftment in mice. | UCB CD34+ lin− | NS |
| HoxA10 | 144 | Increased CFCs from in vitro cultures, block of erythroid differentiation. Engraftment skewed to myeloid in vivo, enriched for transduced cells. | UCB lin−, FL | NS |
| AML1-ETO | 145 | Clonal long-term culture of myeloid cells that retain multilineage potential, CFU-Cs, CAFC activity. Very low levels of human engraftment in mice. | UCB/PBPC CD34+ | NS |
| STAT5A(1*6) | 146 | Increased proliferation of mostly erythroid progenitors, long-term CAFC cultures. Low levels of mostly erythroid lineage engraftment in mice. | UCB CD34+ | NS |
| NRAS(G12D) | 147 | Increased proliferation, cell cycle, increased myeloid differentiation with reduced B and erythroid differentiation in vitro. Improved myeloid skewed multilineage engraftment in mice. | UCB CD34+ | NS |
| TLS-ERG | 148 | Increased proliferation and lifespan, expansion of myeloid progenitors, incomplete myeloid differentiation. One immortalized line with high CD34+ and multilineage potential. Transient engraftment in mice. | UCB lin− | NS |
| BCR-ABL(p210) | 149 | Reduced myeloid colonies and increased erythroid colonies in vitro. A portion of engrafted mice showed myeloproliferation with increasing glyA positivity over time. | UCB lin− | NS, NS-B2M |
| CBFB-MYH11 | 150 | Clonal expansion of myelomonocytic cells with eosinophilia and increased lifespan in vitro with reduced erythroid and B cell potential. Long-term cultures retain modest myeloid restricted engraftment of mice. | UCB CD34+ | NS-B2M |
| TEL-JAK2 | 151 | Increased proliferation and expansion of myeloid and erythroid cells in vitro. Mice engrafted similar to controls, but grafts skewed toward myeloid and erythroid lineages. Myelofibrosis induced in TEL-JAK2 mice. | UCB lin− | NS |
| NUP98-HoxA9 | 152 | Increased expansion, decreased erythroid colonies, increased secondary myeloid colonies, more CAFCs. Proliferative advantage of transduced cells in engrafted mice. | UCB CD34+ | NS, NS-B2M, NSG |
| MLL-AF9 | 94 | Increased lifespan in vitro. pre-B ALL in 8/16 mice, AML in 2/16, mixed lineage in 1/16. | UCB lin− | NS |
| MLL-ENL | 94 | Increased lifespan in vitro. pre-B ALL in vivo. | UCB lin− | NS |
| MLL-AF9 | 93 | Immortal myeloid and lymphoid cultures. B ALL in NS and NS-B2M mice and AML in NSS mice. | UCB CD34+ | NS, NS-B2M, NSS |
| BMI1 | 74 | Enhanced self-renewal (CAFC, LTC-IC) in vitro. Improved engraftment in primary and secondary (very low) mice. | UCB CD34+ | NS |
| TEL-AML1 | 120 | Serial engraftment of an abnormal CD34+CD38-CD19+ cell population, potentially containing pre-LSCs. | UCB CD34+ | NS |
| BCR-ABL+BMI1 | 95 | Increased proliferation, self-renewal (CAFC) in vitro. B-ALL generated in 4/8 mice, transplantable. | UCB CD34+ | NS |
| MLL-AF9+NRAS(G12D) | 9 | Cytokine independent growth in vitro. Faster development of AML in vivo (relative to MLL-AF9 alone), engrafts non-conditioned hosts. | UCB CD34+ | NS, NSG, NSS, NSGS |
| AML1-ETO+NRAS(G12D) | 153 | Increased culture lifespan, serial methylcell replating with erythroid to myeloid shift, cytokine independent growth in vitro. Improved engraftment over AE alone, subcutaneous tumors. | UCB CD34+ | NSG, NSGS |
| MLL-AF9+FLT3-ITD | 103 | Cytokine independent growth in vitro. Faster development of AML in vivo (relative to MLL-AF9 alone), engrafts non-conditioned hosts. | UCB CD34+ | NSG, NSGS |
| BCR-ABL+Ikaros | 92 | Proliferative advantage in vitro. Slight lifespan increase, skewed to erythroid, loss of B cell potential. Expansion of myeloid and erythroid cells in mice. Aggressive AML with disseminated myeloid sarcomas within four weeks; not transplantable. | UCB lin− | NSG, NSGS |
| ERG | 154 | Improved engraftment of transduced cells in thymus of mice, no difference otherwise. | UCB CD34+ | NSG |
| AML1-ETO+c-Kit | 155 | Increased expansion over AE alone, c-kit attenuates AE-induced DNA damage, transient and low levels of human engraftment in mice. | PBPC CD34+ | NSG |
| NUP98-HOXD13+MN1 | 156 | Transient, non-transplantable myeloproliferation with MN1 alone. Aggressive and transplantable AML with NUP98-HoxD13+MN1 only in NSGS mice. | UCB CD34+ | NSG, NSGS |
| PML-RARA | 157 | Reduced myeloid and erythroid colonies in vitro. Sorted CD34+CD38+, but not CD34+CD38- UCB cells led to myeloid skewed engraftment in NOG mice with several abnormal characteristics of APL cells. Low secondary transplantation from unsorted or CD34- cells. | UCB CD34+ | NOG |
FL, fetal liver; NOG, NOD/SCID IL2 receptor γ null; NS, NOD/SCID; NS-B2M, NOD/SCID β-2 microglobulin; NSG, NOD/SCID IL2 receptor γ−/−; NSGS, NOD/SCID IL2RG−/− SCF GM-CSF IL-3; NSS, NOD/SCID SCF GM-CSF IL-3; PBPC, mobilized peripheral blood progenitor cell; UCB, umbilical cord blood.